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.

ALDARA (NDA-020723)

(IMIQUIMOD)

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

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09/25/2024 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Local Skin Reactions

Subsection title revised

Additions and/or revisions underlined:

Local skin reactions including skin weeping or erosion have been reported with ALDARA and can occur after a few applications [see Adverse Reactions (6.1)]. Concomitant use of ALDARA and any other imiquimod products, in the same treatment area, may increase the risk for and severity of local skin reactions.

ALDARA has the potential to exacerbate inflammatory conditions of the skin, including chronic graft versus host disease.

Severe local inflammatory reactions of the female external genitalia can lead to severe vulvar swelling and urinary retention.

Avoid sexual (genital, anal, oral) contact while ALDARA is on the skin.

To reduce the risk of local skin reactions and manage local skin reactions that occur with ADLARA treatment:

Avoid concomitant use of ALDARA with any other imiquimod product in the same treatment area.
Avoid application of ALDARA to skin that is not intact (i.e., any area with an abrasion, cut, burn, rash, infection, or other condition that has altered skin integrity).
An interruption of dosing may be required for local skin reactions [see Dosage and Administration (2.2, 2.3, 2.4)]. Interrupt dosing or discontinue ALDARA for severe vulvar swelling [see Dosage and Administration (2.4)].
If severe local skin reactions occur, instruct patients to remove ALDARA by washing the treatment area with mild soap and water.

5.2 Local Hypopigmentation Reactions

Newly added subsection:

Cases of hypopigmentation, including complete depigmentation, were reported during postmarketing use of ALDARA. In some cases, hypopigmentation and complete depigmentation did not improve or resolve with treatment and persisted for up to 60 months at the time of reporting. Discontinue ALDARA if hypopigmentation develops.

5.3 Systemic Reactions

Additions and/or revisions underlined:

Flu-like signs and symptoms have been reported with use of ALDARA and may accompany, or even precede, local inflammatory reactions [see Adverse Reactions (6.1)]. Signs and symptoms may include malaise, fever, nausea, myalgias, and rigors. Concomitant use of ALDARA and any other imiquimod products may increase the risk for and severity of systemic reactions. Consider an interruption of dosing if systemic reactions occur.

5.4 Ultraviolet Light Exposure Risks

Subsection title revised

Additions and/or revisions underlined:

ALDARA may cause heightened sunburn susceptibility. Avoid or minimize exposure to sunlight (including sunlamps) during use of ALDARA. Instruct patients to use sunscreen and wear protective clothing (e.g., a hat). Advise patients not to use ALDARA until fully recovered from a sunburn.

6 Adverse Reactions

Newly added information

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

Local Skin Reactions [see Warnings and Precautions (5.1)]

Local Hypopigmentation Reactions [see Warnings and Precautions (5.2)]
Systemic Reactions [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

Subsection title revised

Extensive changes; please refer to label for complete information

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Skin and Appendages: exfoliative dermatitis, erythema multiforme, hypertrophic scar, hyperpigmentation, hypopigmentation, including complete depigmentation.

…

8 Use in Specific Populations

8.1 Pregnancy

Pregnancy and Lactation Labeling (PLLR) conversion:

Risk Summary

Available data from case reports and case series of use with imiquimod during pregnancy have not identified a drug- associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are no controlled or large-scale epidemiologic studies and no exposure registries with imiquimod use in pregnant women.

In animal reproduction studies, there were no adverse developmental effects observed after oral administration of imiquimod in pregnant rats and intravenous administration of imiquimod in pregnant rabbits during organogenesis at doses up to 98 times and 407 times, respectively, the maximum recommended human dose (MRHD) (see Data).

The 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 background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

The MRHD was set at 2 packets per treatment of ALDARA (25 mg imiquimod) for the animal multiples of human exposure presented in this label.

Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 1, 5, and 20 mg/kg/day imiquimod were administered during the period of organogenesis to pregnant female rats. In the presence of maternal toxicity, fetal effects noted at 20 mg/kg/day (577 times the MRHD based on AUC comparison) included increased resorptions, decreased fetal body weights, delays in skeletal ossification, bent limb bones, and two fetuses in one litter (2 of 1567 fetuses) demonstrated exencephaly, protruding tongues and low-set ears. No treatment-related effects on embryofetal toxicity or malformation were noted at 5 mg/kg/day (98 times the MRHD based on AUC comparison).

Intravenous doses of 0.5, 1, and 2 mg/kg/day imiquimod were administered during the period of organogenesis to pregnant female rabbits. No treatment-related effects on embryofetal toxicity or malformation were noted at 2 mg/kg/day (1.5 times the MRHD based on BSA comparison), the highest dose evaluated in this study, or 1 mg/kg/day (407 times the MRHD based on AUC comparison).

A combined fertility and peri- and postnatal development study was conducted in rats. Oral doses of 1, 1.5, 3, and

6 mg/kg/day imiquimod were administered to male rats from 70 days prior to mating through the mating period and to female rats from 14 days prior to mating through parturition and lactation. No effects on growth, fertility, reproduction, or postnatal development were noted at doses up to 6 mg/kg/day (87 times the MRHD based on AUC comparison), the highest dose evaluated in this study. In the absence of maternal toxicity, bent limb bones were noted in the F1 fetuses at a dose of 6 mg/kg/day (87 times the MRHD based on AUC comparison). This fetal effect was also noted in the oral rat embryofetal development study conducted with imiquimod. No treatment-related malformations were noted at 3 mg/kg/day (41 times the MRHD based on AUC comparison).

8.2 Lactation

Pregnancy and Lactation Labeling (PLLR) conversion:

Risk Summary

There is no information available on the presence of imiquimod in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production after topical application of ALDARA to women who are breastfeeding. Systemic concentration following topical administration of imiquimod cream is low; therefore, transfer of ALDARA into breastmilk is likely to be low [see Clinical Pharmacology (12.3)]. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for ALDARA and any potential adverse effects on the breastfed infant from ALDARA or from the underlying maternal condition.

Clinical Considerations

Avoid application of ALDARA to areas with increased risk for potential ingestion by or ocular exposure to the breastfeeding child.

8.4 Pediatric Use

Additions and/or revisions underlined:

Actinic Keratosis and Superficial Basal Cell Carcinoma

The safety and effectiveness of ALDARA for the treatment of AK or sBCC in pediatric patients have not been established.

External Genital Warts

The safety and effectiveness of ALDARA for the treatment of EGW in pediatric patients 12 years of age and older have been established. Use of ALDARA for this indication is supported by evidence from adequate and well controlled trials in adults [see Clinical Studies (14.3)]. The safety and effectiveness of ALDARA for the treatment of EGW in pediatric patients less than 12 years of age have not been established.

Molluscum Contagiosum

The safety and effectiveness of ALDARA for the treatment of molluscum contagiosum (MC) in pediatric patients have not been established. Safety and effectiveness of ALDARA was not demonstrated in two randomized, vehicle-controlled, double-blind trials involving 702 pediatric subjects with MC (470 exposed to ALDARA; median age 5 years, range 2–12 years).

Adverse reactions reported in pediatric subject with MC (and not previously reported) included otitis media (5% ALDARA vs. 3% vehicle) and conjunctivitis (3% ALDARA vs. 2% vehicle).

In a pharmacokinetics trial in subjects aged 2 to 12 years with extensive MC involving a least 10% of total body surface area; among the 20 subjects with evaluable laboratory assessments, the median white blood cell (WBC) count decreased by 1.4 x 109/L and the median absolute neutrophil count decreased by 1.42 x 109/L.

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 215 subjects treated with ALDARA in the AK clinical trials, 127 subjects (59%) were 65 years of age or older, while 60 subjects (28%) were 75 years of age or older. Of the 185 subjects treated with ALDARA in the sBCC clinical trials, 65 subjects (35%) were 65 years of age or older, while 25 subjects (14%) were 75 years of age or older. No overall differences in safety or effectiveness of ALDARA have been observed between subjects 65 years of age and older and younger adult subjects.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Important Administration Instructions

Inform all patients of the following: [see Dosage and Administration (2.1)]

ALDARA is for topical use only; avoid contact with the eyes, lips, nostrils, or inside the anus and vagina. Instruct patients to rinse their mouth or eyes with water right away if contact with these areas occur.
Wash hands before and after applying ALDARA.
If an ALDARA dose is missed, apply the next dose at the regularly scheduled time.
Discard and do not reuse partially used packets.

Inform patients with EGW of the following [see Dosage and Administration (2.4)]:

Uncircumcised patients treating warts under the foreskin should retract the foreskin and clean the area daily.
ALDARA may weaken condoms and vaginal diaphragms; therefore, concurrent use is not recommended.
Avoid sexual (genital, anal, oral) contact while ALDARA is on the skin.
Do not bandage or otherwise occlude the treatment area.

Lactation

Advise breastfeeding women to avoid application of ALDARA to areas with increased risk for potential ingestion by or ocular exposure to the breastfeeding child [see Use in Specific Populations (8.2)].

Local Skin Reactions

Inform patients of the following [see Dosage and Administration (2.2, 2.3, 2.4) and Warnings and Precautions (5.1)]:

Local skin reactions may occur during treatment with ALDARA, ranging from mild to severe in intensity and extending beyond the application site onto the surrounding skin, and may require an interruption of dosing.
For female patients being treated for EGW, apply ALDARA at the opening of the vagina, avoiding intravaginal application because local skin reactions may cause difficulty in passing urine.
If severe local skin reactions occur, remove ALDARA by washing the treatment area with mild soap and water.
Contact their healthcare provider promptly if they experience any sign or symptom at the application site that restricts or prohibits their daily activity or makes continued application of ALDARA difficult.
Because of local skin reactions, during treatment and until healed, the treatment area is likely to appear noticeably different from normal skin.

Local Hypopigmentation Reactions

Inform patients that cases of hypopigmentation, including complete depigmentation, were reported during postmarketing use of ALDARA and, in some cases, hypopigmentation and complete depigmentation did not improve or resolve with treatment and persisted for up to 60 months at the time of reporting. Advise patient to inform their healthcare provider if hypopigmentation is observed [see Warnings and Precautions (5.2)].

Systemic Reactions

Inform patients that they may experience flu-like systemic signs and symptoms during treatment with ALDARA and these symptoms may require an interruption of dosing [see Warnings and Precautions (5.3)].

Ultraviolet Light Exposure Risks

Instruct patients to avoid or minimize exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using ALDARA. Instruct patients to use sunscreen and to wear protective clothing, and to not use ALDARA if sunburned [see Warnings and Precautions (5.4)].

PATIENT INFORMATION

Extensive changes; please refer to label for complete information