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Zyclara

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Zyclara

Zyclara

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 treatment.

Systemic Reactions

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 REACTIONS].

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 treatment.

Ultraviolet Light Exposure Risks

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 exposure.

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 Disease

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 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.

Systemic Reactions

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 Keratosis (AK)

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 AND ADMINISTRATION.]

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 Cream application.

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 REACTIONS].

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.

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 surrounding areas.

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.

Nonclinical Toxicology

Carcinogcncsis, Mutagenesis, 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.IX MRHD based on weekly AUC comparisons), 4 mg/kg administered 2X/week in male rats (6. IX MRHD based on weekly AUC comparisons) or 3 mg/kg administered 7X/week to male and female rats (12X MRHD based on weekly AUC comparisons).

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 (2IX 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 test).

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

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 fetus.

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.

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 (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. IX 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 Fl 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).

Nursing Mothers

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.

Pediatric Use

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 demonstrate efficacy.

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 weeping/exudate (2%).

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 by 1.42*109/L.

Geriatric Use

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.

Last reviewed on RxList: 3/1/2012
This monograph has been modified to include the generic and brand name in many instances.

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