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.

ZYCLARA (NDA-022483)

(IMIQUIMOD)

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

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09/16/2024 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Local Skin Reactions

Additions and revisions underlined:

Local skin reactions including skin weeping or erosion have been reported with use of ZYCLARA and can occur after a few applications [see Adverse Reactions (6)]. Concomitant use of ZYCLARA and any other imiquimod products, in the same treatment area, may increase the risk for and severity of local skin reactions.

ZYCLARA Cream 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 to urinary retention.

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

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

Avoid concomitant use of ZYCLARA with any other imiquimod product in the same treatment area.
Avoid application of ZYCLARA 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)]. Interrupt dosing or discontinue ZYCLARA for severe vulvar swelling [see Dosage and Administration (2.3).
If severe local skin reactions occur, instruct patients to remove ZYCLARA by washing the treatment area with mild soap and water.

5.2 Systemic Reactions

Additions and revisions underlined:

Flu-like signs and symptoms have been reported with use of ZYCLARA and may accompany, or even precede, local skin reactions [see Adverse Reactions (6)]. Signs and symptoms may include fatigue, nausea, fever, myalgias, arthralgias, malaise and chills. Concomitant use of ZYCLARA and any other imiquimod products may increase the risk for and severity of systemic reactions.

Lymphadenopathy occurred in 2% of subjects with AK treated with ZYCLARA, 3.75% and in 3% of subjects treated with ZYCLARA, 2.5% and in no patients in the vehicle arm [see Adverse Reactions (6.1)]. This reaction resolved in all subjects by 4 weeks after completion of treatment.

Consider an interruption of dosing if systemic reactions occur.

5.3 Ultraviolet Light Exposure Risks

Additions and revisions underlined:

ZYCLARA may cause heightened sunburn susceptibility. Avoid or minimize exposure to sunlight (including sunlamps) during use of ZYCLARA. Instruct patients to use sunscreen and wear protective clothing (e.g., a hat). Advise patients not to use ZYCLARA 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)]
Systemic Reactions [see Warnings and Precautions (5.2)]

6.1 Clinical Trials Experience

Subsection title revised

Extensive changes; please refer to label

8 Use in Specific Populations

8.1 Pregnancy

Newly added information:

Risk Summary

Available data from case reports and case series have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes when imiquimod is used during pregnancy. 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 28 times and 115 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 defects, loss, and 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 two packets per treatment of ZYCLARA, 3.75%, (18.75 mg imiquimod) for the animal multiples of human exposure presented in this label.

8.2 Lactation

Newly added information:

Risk Summary

There is no information regarding the presence of topically administered imiquimod in human milk, the effects on the breastfed infant, or the effects on milk production. Systemic concentration following topical administration of imiquimod cream is low; therefore, transfer of ZYCLARA into breastmilk is likely to be low [see Clinical Pharmacology (12.3)].

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZYCLARA and any potential adverse effects on the breastfed infant from ZYCLARA or from the underlying maternal condition.

Clinical Considerations

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

8.4 Pediatric Use

Additions and revisions underlined:

Actinic Keratosis

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

External Genital Warts

The safety and effectiveness of ZYCLARA for the treatment of EGW in pediatric patients 12 years of age and older have been established. Use of ZYCLARA for this indication is supported by evidence from adequate and well controlled trials in adults and pediatric subjects [see Clinical Studies (14.2)]. The safety and effectiveness of ZYCLARA 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 ZYCLARA for the treatment of molluscum contagiosum (MC) in pediatric patients have not been established. Safety and effectiveness of imiquimod cream, 5% was not demonstrated in two randomized, vehicle-controlled, double-blind trials involving 702 pediatric subjects with MC (470 exposed to imiquimod cream; median age 5 years, range 2-12 years).

Adverse reactions reported in pediatric subjects with MC (and not previously reported) included otitis media (5% imiquimod cream vs. 3% vehicle) and conjunctivitis (3% imiquimod cream 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 revisions underlined:

Of the 320 subjects treated with ZYCLARA in the AK clinical trials, 150 subjects (47%) were 65 years of age or older. No overall differences in safety or effectiveness of ZYCLARA have been observed between subjects 65 years of age and older and younger adult subjects.

Of the 400 subjects treated with ZYCLARA in the EGW clinical studies, 5 subjects (1%) were 65 years or older. Clinical studies of ZYCLARA for EGW did not include sufficient numbers of subjects aged 65 years of age and older to determine whether they respond differently from younger adult subjects.

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

PATIENT COUNSELING INFORMATION

Additions and 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)]:

ZYCLARA is for topical use only and 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 their hands before and after applying ZYCLARA.
If a ZYCLARA dose is missed, apply the next dose at the regularly scheduled time.
Discard and do not reuse partially used packets.
Discard pump bottles after completion of a full treatment course.

Inform patients with EGW of the following [see Dosage and Administration 2.3 and Warnings and Precautions (5.1)]:

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

Lactation

Advise breastfeeding women to avoid application of ZYCLARA 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) and Warnings and Precautions (5.1)]:

Local skin reactions may occur during treatment with ZYCLARA, 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 ZYCLARA 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 ZYCLARA 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 ZYCLARA 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 and Hyperpigmentation

Inform patients that localized hypopigmentation and hyperpigmentation have been reported following use of imiquimod cream and these skin color changes may be permanent in some patients [see Adverse Reactions (6.2)].

Systemic Reactions

Inform patients that they may experience flu-like systemic signs and symptoms during treatment with ZYCLARA and these symptoms may require an interruption of dosing [see Warnings and Precautions (5.2)].

Ultraviolet Light Exposure Risks

Instruct patients to avoid or minimize exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using ZYCLARA. Instruct patients to use protective clothing and to not use ZYCLARA if sunburned [see Warnings and Precautions (5.3)].

Patient Information

Additions and revisions underlined:

Important: For use on the skin only (topical). Do not use ZYCLARA Cream in or near your lips, mouth, eyes or

inside your anus, vagina, or nose.

. . .

It is not known if ZYCLARA Cream is safe and effective in the treatment of:

• human papilloma virus (HPV) disease of the urethra, the inside of the vagina (intravaginal), cervix, rectum, or

inside of the anus (intra-anal)

• actinic keratosis, when treated with more than one 2-cycle treatment course in the same affected area

• people with extreme sensitivity to sunlight (xeroderma pigmentosum)

• a type of skin cancer called superficial basal cell carcinoma

• people who have a weakened immune system

. . .

Before using ZYCLARA Cream, tell your healthcare provider about all of your medical conditions, including if

you:

• have problems with your immune system, including autoimmune disease or long-lasting (chronic) graft versus host

disease

• are being treated or have been treated with other medicines or surgery. You should not use ZYCLARA Cream until

your skin has healed from other treatments.

• have other skin problems or sunburn.

• are pregnant or plan to become pregnant. It is not known if ZYCLARA Cream can harm your unborn baby.

• are breastfeeding or plan to breastfeed. It is not known if ZYCLARA Cream passes into your breast milk. If you

breastfeed during treatment with ZYCLARA Cream, avoid contact of your treated skin with your baby’s mouth or

eyes. Talk to your healthcare provider about the best way to feed your baby if you use ZYCLARA Cream.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter

medicines, vitamins, and herbal supplements.

How should I use ZYCLARA Cream?

• Use ZYCLARA Cream exactly as your healthcare provider tells you to use it.

• Your healthcare provider should show you how to apply ZYCLARA Cream.

• Apply ZYCLARA Cream 1 time a day just before your bedtime. Do not use more ZYCLARA Cream than you need

to cover the affected area. Using too much ZYCLARA Cream, or using it too often, or for too long can increase

your chances for having a severe skin reaction or other side effects.

• Your healthcare provider may prescribe ZYCLARA Cream in a packet or pump.

ZYCLARA Cream packet:

o Open a packet of ZYCLARA Cream just before use.

o After applying ZYCLARA Cream, the opened packet should be thrown away even if all the ZYCLARA Cream

was not used.

ZYCLARA Cream pump:

o Remove the cap.

o Before using the pump for the first time only, prime the pump by pressing the top of the pump all the way

down repeatedly until the cream appears. The cream obtained from priming should be dispensed into a tissue

and then thrown away (discarded). The pump is now primed and is ready to use. You will not have to repeat this

priming process during your treatment.

o When dispensing the cream, slightly tilt the pump as shown.

Reference ID: 5447180

o Firmly press the top of the pump all the way down to dispense the cream onto your hand or fingertip.

Applying ZYCLARA Cream:

• Wash the area where ZYCLARA Cream will be applied with mild soap and water.

• Allow the area to dry.

• Wash your hands well.

• Apply a thin layer of ZYCLARA Cream only to the affected area(s) to be treated.

• Rub ZYCLARA Cream in all the way until you cannot see the cream on the affected area(s).

• Wash your hands well after applying ZYCLARA Cream.

• After about 8 hours, wash the treated area(s) with mild soap and water. Do not leave ZYCLARA Cream on your

skin longer than prescribed. If you forget to apply ZYCLARA Cream, apply the next dose of ZYCLARA Cream at

your regularly scheduled time.

When using ZYCLARA Cream for actinic keratosis:

• Do not get ZYCLARA Cream in or near your lips, mouth, or eyes, or inside your nose.

• If you get ZYCLARA Cream in your mouth or in your eyes, rinse well with water right away.

• Apply ZYCLARA Cream to the skin of the affected area for 2 weeks, then stop using for 2 weeks, then apply again

for 2 weeks.

• If you have been prescribed ZYCLARA Cream packets, do not use more than 2 packets for each daily application.

• If you have been prescribed ZYCLARA Cream pump, do not dispense more than 2 pumps for each daily

application.

When using ZYCLARA Cream for external genital or perianal warts:

• Do not get ZYCLARA Cream in your anus or vagina.

• Treatment should continue until the warts are completely gone or for up to 8 weeks. ZYCLARA Cream will not cure

your genital or perianal warts. New warts may develop during treatment with ZYCLARA Cream.

• Uncircumcised males treating warts under their penis foreskin must pull their foreskin back and clean before

treatment and clean daily during treatment.

• Females treating genital warts must be careful when applying ZYCLARA Cream around the vaginal opening.

• If you have been prescribed ZYCLARA Cream packets, do not use more than 1 packet for each daily application.

• If you have been prescribed ZYCLARA Cream pump, do not dispense more than 1 pump for each daily

application.

What should I avoid while using ZYCLARA Cream?

• Do not cover the treated area with bandages or other closed dressings. Cotton gauze dressings can be used, if

needed. Cotton underwear can be worn after applying ZYCLARA Cream to the genital or perianal area.

• Do not use sunlamps or tanning beds, and avoid sunlight as much as possible during treatment with ZYCLARA

Cream. Use sunscreen and wear protective clothing if you go outside during daylight.

• Do not have sexual contact including genital, anal, or oral sex when ZYCLARA Cream is on your genital or

perianal skin. ZYCLARA Cream may weaken condoms and vaginal diaphragms. This means they may not work as

well to prevent pregnancy.

• Avoid using ZYCLARA Cream and any other imiquimod products in the same treatment area. They have the same

active ingredients (imiquimod) and may increase your risk for side effects.

What are the possible side effects of ZYCLARA Cream?

ZYCLARA Cream may cause serious side effects, including:

• Treatment site skin reactions. Skin reactions including drainage (weeping) or breakdown of the outer layer of

your skin (erosion) can happen after a few applications of ZYCLARA Cream. Swelling outside of the vagina (vulvar

swelling) may happen in females. Females should take special care if applying the cream at the opening of the

vagina because skin reactions can cause pain or swelling, and may cause problems passing urine. If you get skin

reactions, wash the treated area with mild soap and water.

Stop ZYCLARA Cream right away and call your healthcare provider if you get any skin reactions that affect

your daily activities, or that do not go away.

• Flu-like symptoms. Tell your healthcare provider if you get tiredness, nausea, vomiting, fever, chills, muscle pain,

and joint pain.

Your healthcare provider may temporarily stop or completely stop your treatment with ZYCLARA Cream if you develop

treatment site skin reactions or flu-like symptoms.