Included as part of the PRECAUTIONS section.
Local Skin Reactions
Intense local skin reactions
including skin weeping or erosion can occur after a few applications of ZYCLARA
Cream and may require an interruption of dosing [see DOSAGE AND
ADMINISTRATION and ADVERSE 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.
Severe vulvar swelling can lead to urinary retention. Dosing should be
interrupted or discontinued for severe vulvar swelling.
Administration of ZYCLARA Cream
is not recommended until the skin is healed from any previous drug or surgical
Flu-like signs and symptoms may
accompany, or even precede, local skin reactions and may include fatigue,
nausea, fever, myalgias, arthralgias, malaise and chills. An interruption of
dosing and an assessment of the patient should be considered [see ADVERSE
Lymphadenopathy occurred in 2%
of subjects with actinic keratosis treated with ZYCLARA Cream, 3.75% and in 3%
of subjects treated with ZYCLARA Cream, 2.5% [see ADVERSE REACTIONS].
This reaction resolved in all subjects by 4 weeks after completion of
Ultraviolet Light Exposure
Exposure to sunlight (including
sunlamps) should be avoided or minimized during use of ZYCLARA Cream. Patients
should be warned to use protective clothing (e.g., a hat) when using ZYCLARA
Cream. Patients with sunburn should be advised not to use ZYCLARA Cream until
fully recovered. Patients who may have considerable sun exposure, e.g., due to
their occupation, and those patients with inherent sensitivity to sunlight
should exercise caution when using ZYCLARA Cream.
In an animal
photo-carcinogenicity study, imiquimod cream shortened the time to skin tumor
formation [see Nonclinical Toxicology]. The enhancement of ultraviolet
carcinogenicity is not necessarily dependent on phototoxic mechanisms.
Therefore, patients should minimize or avoid natural or artificial sunlight
Increased Risk Of Adverse
Reactions With Concomitant Imiquimod Use
Concomitant use of ZYCLARA
Cream and any other imiquimod products, in the same treatment area, should be
avoided since they contain the same active ingredient (imiquimod) and may
increase the risk for and severity of local skin reactions.
The safety of concomitant use
of ZYCLARA Cream and any other imiquimod products has not been established and
should be avoided since they contain the same active ingredient (imiquimod) and
may increase the risk for and severity of systemic reactions.
Immune Cell Activation In Autoimmune
ZYCLARA Cream should be used
with caution in patients with pre-existing autoimmune conditions because
imiquimod activates immune cells [see CLINICAL PHARMACOLOGY].
Patient Counseling Information
See FDA-approved patient
labeling (PATIENT INFORMATION)
Instructions For Administration
ZYCLARA Cream should be used as
directed by a physician. ZYCLARA Cream is for external use only. Contact with
the eyes, lips, nostrils, anus and vagina should be avoided [see INDICATIONS
AND USAGE and DOSAGE AND ADMINISTRATION].
The treatment area should not
be bandaged or otherwise occluded. Partially-used packets should be discarded
and not reused. Pumps should be discarded after completion of a full treatment
course. The prescriber should demonstrate the proper application technique to
maximize the benefit of ZYCLARA Cream therapy.
It is recommended that patients
wash their hands before and after applying ZYCLARA Cream.
Local Skin Reactions
Patients may experience local
skin reactions during treatment with ZYCLARA Cream. Potential local skin
reactions include erythema, edema, erosions/ulcerations, weeping/exudate, flaking/scaling/dryness,
and scabbing/crusting. These reactions can range from mild to severe in
intensity and may extend beyond the application site onto the surrounding skin.
Patients may also experience application site reactions such as itching,
irritation or pain [see ADVERSE REACTIONS].
Local skin reactions may be of
such an intensity that patients may require rest periods from treatment.
Treatment with ZYCLARA Cream can be resumed after the skin reaction has
subsided, as determined by the physician. However, for actinic keratosis, each
treatment cycle should not be extended beyond 2 weeks due to missed doses or
rest periods. For external genital warts, treatment should not be extended
beyond 8 weeks due to missed doses or rest periods. Patients should contact
their physician promptly if they experience any sign or symptom at the
application site that restricts or prohibits their daily activity or makes
continued application of the cream difficult.
Because of local skin
reactions, during treatment and until healed, the treatment area is likely to
appear noticeably different from normal skin. Localized hypopigmentation and
hyperpigmentation have been reported following use of imiquimod cream. These
skin color changes may be permanent in some patients.
Patients may experience
flu-like systemic signs and symptoms during treatment with ZYCLARA Cream.
Systemic signs and symptoms may include fatigue, nausea, fever, myalgia,
malaise, arthralgia, and chills [see ADVERSE REACTIONS]. An interruption
of dosing and an assessment of the patient should be considered.
Patients Being Treated For Actinic
Dosing is once daily before
bedtime to the skin of the affected area (entire face or balding scalp) for two
2-week treatment cycles separated by a 2-week no-treatment period. However, the
treatment period should not be extended beyond two 2-week treatment cycles due
to missed doses or rest periods. Treatment should continue for the full
treatment course even if all actinic keratoses appear to be gone [see DOSAGE
It is recommended that patients
wash their hands before and after applying ZYCLARA Cream. Before applying the
cream, the patient should wash the treatment area with mild soap and water and
allow the area to dry thoroughly.
It is recommended that the
treatment area be washed with mild soap and water 8 hours following ZYCLARA
Most patients using ZYCLARA
Cream for the treatment of AK experience erythema, flaking/scaling/dryness and
scabbing/crusting at the application site with normal dosing [see ADVERSE
Use of sunscreen is encouraged,
and patients should minimize or avoid exposure to natural or artificial
sunlight (tanning beds or UVA/B treatment) while using ZYCLARA Cream [see
WARNINGS AND PRECAUTIONS].
Additional lesions may become
apparent in the treatment area during treatment [see Clinical Studies].
Patients Being Treated For External
Genital Warts (EGW)
Dosing is once daily before
bedtime to the skin of the affected wart areas. ZYCLARA Cream treatment should
continue until there is total clearance of the genital/perianal warts or for up
to 8 weeks.
It is recommended that the
treatment area be washed with mild soap and water approximately 8 hours
following ZYCLARA Cream application.
It is common for patients to
experience local skin reactions such as erythema, erosion, exudate,
flaking/scaling, scabbing/crusting and edema at the site of application or
Sexual (genital, anal, oral)
contact should be avoided while ZYCLARA Cream is on the skin. Application of
ZYCLARA Cream in the vagina is considered internal and should be avoided.
Female patients should take special care if applying the cream at the opening
of the vagina because local skin reactions on the delicate moist surfaces can
result in pain or swelling, and may cause difficulty in passing urine.
Uncircumcised males treating
warts under the foreskin should retract the foreskin and clean the area daily.
New warts may develop during
therapy, as ZYCLARA Cream is not a cure.
The effect of ZYCLARA Cream on
the transmission of genital/perianal warts is unknown.
ZYCLARA Cream may weaken
condoms and vaginal diaphragms, therefore concurrent use is not recommended.
Should severe local skin
reaction occur, the cream should be removed by washing the treatment area with
mild soap and water.
Impairment Of Fertility
In an oral (gavage) rat
carcinogenicity study, imiquimod was administered to Wistar rats on a 2X/week
(up to 6 mg/kg/day) or daily (3 mg/kg/day) dosing schedule for 24 months. No
treatment related tumors were noted in the oral rat carcinogenicity study up to
the highest doses tested in this study of 6 mg/kg administered 2X/week in
female rats (7.1X MRHD based on weekly AUC comparisons), 4 mg/kg administered
2X/week in male rats (6.1X MRHD based on weekly AUC comparisons) or 3 mg/kg
administered 7X/week to male and female rats (12X MRHD based on weekly AUC
In a dermal mouse
carcinogenicity study, imiquimod cream (up to 5 mg/kg/application imiquimod or
0.3% imiquimod cream) was applied to the backs of mice 3X/week for 24 months. A
statistically significant increase in the incidence of liver adenomas and
carcinomas was noted in high dose male mice compared to control male mice (21X
MRHD based on weekly AUC comparisons). An increased number of skin papillomas
was observed in vehicle cream control group animals at the treated site only.
In a 52-week dermal
photo-carcinogenicity study, the median time to onset of skin tumor formation
was decreased in hairless mice following chronic topical dosing (3X/week; 40
weeks of treatment followed by 12 weeks of observation) with concurrent
exposure to UV radiation (5 days per week) with vehicle alone. No additional
effect on tumor development beyond the vehicle effect was noted with the
addition of the active ingredient, imiquimod, to the vehicle cream.
Imiquimod revealed no evidence
of mutagenic or clastogenic potential based on the results of five in vitro
genotoxicity tests (Ames assay, mouse lymphoma L5178Y assay, Chinese hamster
ovary cell chromosome aberration assay, human lymphocyte chromosome aberration
assay and SHE cell transformation assay) and three in vivo genotoxicity tests
(rat and hamster bone marrow cytogenetics assay and a mouse dominant lethal
Daily oral administration of
imiquimod to rats, throughout mating, gestation, parturition and lactation,
demonstrated no effects on growth, fertility or reproduction, at doses up to
25X MRHD based on AUC comparisons.
Use In Specific Populations
Pregnancy Category C
There are no adequate and
well-controlled studies in pregnant women. ZYCLARA Cream should be used during
pregnancy only if the potential benefit justifies the potential risk to the
The animal multiples of human
exposure calculations were based on daily dose comparisons for the reproductive
toxicology studies described in this section and in Section 13.1. The animal
multiples of human exposure were based on weekly dose comparisons for the
carcinogenicity studies described in Section 13.1. For the animal multiple of
human exposure ratios presented in this section and Section 13.1, the Maximum
Recommended Human Dose (MRHD) was set at 2 packets (500 mg cream) per treatment
of actinic keratosis with ZYCLARA Cream (imiquimod 3.75%, 18.75 mg imiquimod)
for BSA comparison. The maximum human AUC value obtained in the treatment of
external genital and perianal warts was higher than that obtained in the
treatment of actinic keratosis and was used in the calculation of animal
multiples of MRHD that were based on AUC comparison.
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
(gestational days 6–15) to pregnant female rats. In the presence of maternal
toxicity, fetal effects noted at 20 mg/kg/day (163X MRHD based on AUC
comparisons) 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 teratogenicity
were noted at 5 mg/kg/day (28X MRHD based on AUC comparisons).
Intravenous doses of 0.5, 1 and
2 mg/kg/day imiquimod were administered during the period of organogenesis
(gestational days 6–18) to pregnant female rabbits. No treatment related
effects on embryofetal toxicity or teratogenicity were noted at 2 mg/kg/day
(2.1X MRHD based on BSA comparisons), the highest dose evaluated in this study,
or 1 mg/kg/day (115X MRHD based on AUC comparisons).
A combined fertility and peri-
and post-natal 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 post-natal development were noted at doses up to 6 mg/kg/day
(25X MRHD based on AUC comparisons), 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 (25X MRHD based on AUC comparisons). This
fetal effect was also noted in the oral rat embryofetal development study
conducted with imiquimod. No treatment related effects on teratogenicity were
noted at 3 mg/kg/day (12X MRHD based on AUC comparisons).
It is not known whether
imiquimod is excreted in human milk following use of ZYCLARA Cream. Because
many drugs are excreted in human milk, caution should be exercised when ZYCLARA
Cream is administered to nursing women.
AK is a condition not generally
seen within the pediatric population. The safety and effectiveness of ZYCLARA
Cream for AK in patients less than 18 years of age have not been established.
Safety and effectiveness in
patients with external genital/perianal warts below the age of 12 years have
not been established.
Imiquimod 5% cream was
evaluated in two randomized, vehicle-controlled, double-blind trials involving
702 pediatric subjects with molluscum contagiosum (MC) (470 exposed to
imiquimod; median age 5 years, range 2-12 years). Subjects applied imiquimod
cream or vehicle 3 times weekly for up to 16 weeks. Complete clearance (no MC lesions)
was assessed at Week 18. In Study 1, the complete clearance rate was 24%
(52/217) in the imiquimod cream group compared with 26% (28/106) in the vehicle
group. In Study 2, the clearance rates were 24% (60/253) in the imiquimod cream
group compared with 28% (35/126) in the vehicle group. These studies failed to
Similar to the studies
conducted in adults, the most frequently reported adverse reaction from 2
studies in children with molluscum contagiosum was application site reaction.
Adverse events which occurred more frequently in imiquimod-treated subjects
compared with vehicle-treated subjects generally resembled those seen in
studies in indications approved for adults and also included otitis media (5%
imiquimod vs. 3% vehicle) and conjunctivitis (3% imiquimod vs. 2% vehicle).
Erythema was the most
frequently reported local skin reaction. Severe local skin reactions reported
by imiquimod-treated subjects in the pediatric studies included erythema (28%),
edema (8%), scabbing/crusting (5%), flaking/scaling (5%), erosion (2%) and
Systemic absorption of
imiquimod across the affected skin of 22 subjects aged 2 to 12 years with
extensive MC involving at least 10% of the total body surface area was observed
after single and multiple doses at a dosing frequency of 3 applications per
week for 4 weeks. The investigator determined the dose applied, either 1, 2 or
3 packets per dose, based on the size of the treatment area and the subject's
weight. The overall median peak serum drug concentrations at the end of week 4
was between 0.26 and 1.06 ng/mL except in a 2-year old female who was
administered 2 packets of study drug per dose, had a Cmax of 9.66 ng/mL after multiple dosing. Children aged 2-5
years received doses of 12.5 mg (one packet) or 25 mg (two packets) of
imiquimod and had median multiple-dose peak serum drug levels of
approximately 0.2 or 0.5 ng/mL, respectively. Children aged 6-12 years received
doses of 12.5 mg, 25 mg, or 37.5 mg (three packets) and had median multiple
dose serum drug levels of approximately 0.1, 0.15, or 0.3 ng/mL, respectively.
Among the 20 subjects with evaluable laboratory assessments, the median WBC
count decreased by 1.4*109/L and the median absolute neutrophil count decreased
Of the 320 subjects treated
with ZYCLARA Cream in the AK clinical studies, 150 subjects (47%) were 65 years
or older. No overall differences in safety or effectiveness were observed
between these subjects and younger subjects.
Clinical studies of ZYCLARA
Cream for EGW did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. Of the 400
subjects treated with ZYCLARA Cream, 3.75% in the EGW clinical studies, 5
subjects (1%) were 65 years or older.