1.1 Actinic Keratosis

ZYCLARA, 2.5% and 3.75% are indicated for the topical treatment of clinically typical, visible or palpable actinic keratoses (AK) of the face or balding scalp in immunocompetent adults.

1.2 External Genital Warts

ZYCLARA, 3.75% is indicated for the topical treatment of external genital and perianal warts (EGW) in immunocompetent patients 12 years of age and older.

2.1 Important Dosage and Administration Instructions

ZYCLARA is for topical use only. ZYCLARA is not for oral, ophthalmic, intra-anal or intravaginal use. Instruct patients on proper application technique.

Wash hands before and after applying ZYCLARA.

Prime the ZYCLARA pump bottle before first use by repeatedly depressing the actuator until the cream is dispensed. It is not necessary to repeat this priming process during treatment.

If a ZYCLARA dose is missed, apply the next dose at the regularly scheduled time.

Avoid contact with the eyes, lips, nostrils, or inside the anus and vagina.

Prescribe no more than 2 boxes (56 packets) or two 7.5 g bottle pumps of ZYCLARA for the entire treatment course for AK or EGW.

Discard partially used packets and do not reuse. Discard pump bottles after completion of a full treatment course.

2.2 Dosage and Administration for Actinic Keratosis

Use ZYCLARA, 2.5% or 3.75% for the treatment of AK. Apply a thin layer of ZYCLARA once daily before bedtime to the area with AK (either entire face or balding scalp) for two 2-week treatment cycles separated by a 2-week no-treatment period. Rub in until the cream is no longer visible. Apply up to 0.5 grams (two packets or two full actuations of the pump) of ZYCLARA at each application. Leave ZYCLARA on the skin for approximately 8 hours and then remove with mild soap and water.

For local skin reactions, a dosage interruption of several days may be taken if required based on the patient’s discomfort or severity of the local skin reaction [see Warnings and Precautions (5.1)]. Do not extend either 2-week treatment cycle due to missed doses or rest periods .Assess response to treatment after resolution of local skin reactions.

A transient increase in lesion counts may be observed during treatment; however, continue dosing as prescribed. Continue treatment for the full treatment course even if all AK appear to be gone.

2.3 Dosage and Administration for External Genital Warts

Use ZYCLARA, 3.75% for the treatment of EGW. Apply a thin layer of ZYCLARA cream once daily before bedtime to EGW until total clearance or for up to 8 weeks. To treat the wart area, use up to 0.25 grams (one packet or one full actuation of the pump) at each application. Leave ZYCLARA on the skin for approximately 8 hours and then remove with mild soap and water.

For local skin reactions, a dosage interruption of several days may be taken if required by the patient's discomfort or severity of the local skin reaction; resume treatment once the reaction subsides [see Warnings and Precautions (5.1)] .

Non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions.

Inform uncircumcised patients treating warts under the foreskin to retract the foreskin and clean the area daily.

ZYCLARA may weaken condoms and vaginal diaphragms, therefore, concurrent use is not recommended.

5.1 Local Skin Reactions

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

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

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.

5.4 Immune Cell Activation in Autoimmune Disease

Imiquimod activates immune cells [see Clinical Pharmacology (12.2)] . Carefully monitor patients with pre-existing autoimmune conditions who are using ZYCLARA.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Actinic Keratosis

The data described below reflect exposure to ZYCLARA or vehicle in 479 subjects with AK enrolled in two double-blind, vehicle-controlled trials (Studies AK1 and AK2) [see Clinical Studies (14.1)] . Subjects applied up to two packets of ZYCLARA, 3.75%, ZYCLARA, 2.5%, or vehicle once daily, to the skin of the affected area (either entire face or balding scalp) for two 2-week treatment cycles separated by a 2-week no treatment period. Selected adverse reactions are listed in Table 1.

Local skin reactions were recorded as adverse reactions if they extended beyond the treatment area, or required any medical intervention, or resulted in patient discontinuation from the trial. The incidence and severity of selected local skin reactions are shown in Table 2.

In the AK trials, 11% (17/160) of subjects in the ZYCLARA, 3.75% arm, 7% (11/160) of subjects in the ZYCLARA, 2.5% arm, and 0% in the vehicle arm required rest periods due to adverse local skin reactions.

Other adverse reactions observed in subjects treated with ZYCLARA included: application site bleeding, application site swelling, chills, dermatitis, herpes zoster, insomnia, lethargy, myalgia, pancytopenia, pruritus, squamous cell carcinoma, and vomiting.

External Genital Warts

In two double-blind, placebo-controlled trials 602 subjects with EGW applied up to one packet of ZYCLARA, 3.75% or vehicle to all warts once daily for up to 8 weeks (Studies EGW1 and EGW2) [see Clinical Studies (14.2)] .

The most frequently reported adverse reactions were application site reactions and local skin reactions. Selected adverse reactions are listed in Table 3.

*Percentage based on female population of 6/216 for ZYCLARA, 3.75% and 2/106 for vehicle

Local skin reactions were recorded as adverse reactions if they extended beyond the treatment area, or required any medical intervention, or resulted in patient discontinuation from the trial. The incidence and severity of selected local skin reactions are shown in Table 4.

The frequency and severity of local skin reactions were similar in both sexes, with the following exceptions: a) flaking/scaling occurred in 40% of males and in 26% of females and b) scabbing/crusting occurred in 34% of males and in 18% of females.

In Studies EGW1 and EGW2, 32% (126/400) of subjects who used ZYCLARA, 3.75% and 2% (4/202) of subjects who used vehicle discontinued treatment temporarily (required rest periods) due to adverse local skin reactions, and 1% (3/400) of subjects who used ZYCLARA, 3.75% discontinued treatment permanently due to local skin/application site reactions.

Other adverse reactions reported in subjects treated with ZYCLARA, 3.75% included: rash, back pain, application site rash, application site cellulitis, application site excoriation, application site bleeding, scrotal pain, scrotal erythema, scrotal ulcer, scrotal edema, sinusitis, nausea, pyrexia, and influenza-like symptoms.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of imiquimod. 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.

Application Site Disorders: tingling at the application site

Body as a Whole: angioedema

Cardiovascular: capillary leak syndrome, cardiac failure, cardiomyopathy, pulmonary edema, arrhythmias (tachycardia, supraventricular tachycardia, atrial fibrillation, palpitations), chest pain, ischemia, myocardial infarction, syncope

Endocrine: thyroiditis

Gastrointestinal System Disorders: abdominal pain

Hematological: decreases in red cell, white cell and platelet counts (including idiopathic thrombocytopenic purpura), lymphoma

Hepatic: abnormal liver function

Infections and Infestations: herpes simplex

Musculoskeletal System Disorders: arthralgia

Neuropsychiatric: agitation, cerebrovascular accident, convulsions (including febrile convulsions), depression, insomnia, multiple sclerosis aggravation, paresis, suicide

Respiratory: dyspnea

Urinary System Disorders: proteinuria, urinary retention, dysuria

Skin and Appendages: exfoliative dermatitis, erythema multiforme, hyperpigmentation, hypertrophic scar, hypopigmentation

Vascular: Henoch-Schönlein purpura syndrome

8.1 Pregnancy

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.

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 (163 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 (28 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 (2.1 times the MRHD based on BSA comparison), the highest dose evaluated in this study, or 1 mg/kg/day (115 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 (25 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 (25 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 (12 times the MRHD based on AUC comparison).

8.2 Lactation

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

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 10 9/L and the median absolute neutrophil count decreased by 1.42 x 10 9/L.

8.5 Geriatric Use

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.

12.1 Mechanism of Action

The mechanism of action of ZYCLARA in the treatment of AK and EGW is unknown.

12.2 Pharmacodynamics

The pharmacodynamics of ZYCLARA are unknown.

Imiquimod is a Toll-like receptor 7 agonist that activates immune cells. Topical application to skin is associated with increases in markers for cytokines and immune cells.

12.3 Pharmacokinetics

Absorption

Following dosing with two packets of ZYCLARA, 3.75% once daily (18.75 mg imiquimod/day) for up to 3 weeks, systemic absorption of imiquimod was observed in all subjects when ZYCLARA was applied to the face and/or scalp in 17 subjects with at least 10 AK lesions. The mean peak serum imiquimod concentration at the end of the trial was approximately 0.323 ng/mL. The median time to maximal concentrations (T max) occurred at 9 hours after dosing. Based on the plasma half-life of imiquimod observed at the end of the trial, 29.3±17.0 hours, steady-state concentrations can be anticipated to occur by Day 7 with once-daily dosing.

Systemic absorption of imiquimod (up to 9.4 mg [one packet]) across the affected skin of 18 subjects with EGW was observed with once daily dosing for 3 weeks in all subjects. The subjects had either a minimum of 8 warts (range 8-93) or a surface area involvement of greater than 100 mm 2(range 15-620 mm 2) at trial entry. The mean peak serum imiquimod concentration at Day 21 was 0.488 +/- 0.368 ng/mL. The median time to maximal concentrations (T max) occurred 12 hours after dosing. Based on the plasma half-life of imiquimod observed at the end of the trial, 24.1 +/- 12.4 hours, steady-state concentrations can be anticipated to occur by Day 7 with once daily dosing. Because of the small number of subjects present (13 males, 5 females) it was not possible to select out or do an analysis of absorption based on sex/site of application.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In an oral (gavage) rat carcinogenicity study, imiquimod was administered to Wistar rats on a 2 times per 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 2 times per week in female rats (7.1 times the MRHD based on weekly AUC comparison), 4 mg/kg administered 2 times per week in male rats (6.1 times the MRHD based on weekly AUC comparison) or 3 mg/kg administered 7 times per week to male and female rats (12 times the MRHD based on weekly AUC comparison).

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 3 times per 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 (21 times the MRHD based on weekly AUC comparison). An increased number of skin papillomas was observed in vehicle cream control group animals at the treated site only.

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 25 times the MRHD based on AUC comparison.

14.1 Actinic Keratosis

In two double-blind, randomized, vehicle-controlled clinical trials, 479 subjects with AK were treated with ZYCLARA, 3.75%, ZYCLARA, 2.5%, or vehicle (Studies AK1 and AK2). Trials enrolled subjects 18 years of age or older with 5 to 20 typical visible or palpable AK lesions of the face or scalp. ZYCLARA or vehicle was applied to either the entire face (excluding ears) or balding scalp once daily for two 2-week treatment cycles separated by a 2-week no-treatment period. Subjects then continued in the trial for an 8-week follow-up period during which they returned for clinical observations and safety monitoring. Trial subjects ranged from 36 to 90 years of age and 54% had Fitzpatrick skin type I or II. All ZYCLARA-treated subjects were White.

On a scheduled dosing day, up to two packets of the trial cream were applied to the entire treatment area prior to normal sleeping hours and left on for approximately 8 hours. Efficacy was assessed by AK lesion counts at the 8-week post-treatment visit. All AKs in the treatment area were counted, including baseline lesions as well as lesions which appeared during therapy.

Complete clearance required absence of any lesions including those that appeared during therapy in the treatment area. Complete and partial clearance rates are shown in Tables 5 and 6 below. Partial clearance rate was defined as the percentage of subjects in whom the number of baseline AKs was reduced by 75% or more. The partial clearance rate was measured relative to the numbers of AK lesions at baseline.

During treatment, 86% (138/160) of ZYCLARA 3.75% subjects and 84% (135/160) of ZYCLARA, 2.5% subjects experienced a transient increase in lesions evaluated as AK relative to the number present at baseline within the treatment area.

14.2 External Genital Warts

In two double-blind, randomized, placebo-controlled clinical trials, 601 subjects with EGW were treated with ZYCLARA, 3.75% or a matching vehicle (Studies EGW1 and EGW2). Trials enrolled subjects aged from 15 to 81 years. The baseline wart area ranged from 6 to 5,579 mm 2(median 60 mm 2) and the baseline wart count ranged from 2 to 48 warts. Most subjects had two or more treated anatomic areas at baseline. Anatomic areas included: inguinal, perineal, and perianal areas (both sexes); the glans penis, penis shaft, scrotum, and foreskin (in males); and the vulva (in females). Up to one packet of trial cream was applied once daily. The trial cream was applied to all warts prior to normal sleeping hours and left on for approximately 8 hours. Subjects continued applying the trial cream for up to 8 weeks, stopping if they achieved complete clearance of all (baseline and new) warts in all anatomic areas. Subjects who achieved complete clearance of all warts at any time up to the Week 16 visit entered a 12-week follow-up period to assess recurrence.

Complete clearance was defined as clearance of all warts (baseline and new) in all anatomic areas within 16 weeks from baseline. The complete clearance rates are shown in Table 7. The proportions of subjects who achieved complete clearance at or before a given week (cumulative proportion) for the combined studies are shown in Figure 1. Complete clearance rates by sex for the combined studies are shown in Table 8.

Figure 1: Cumulative Proportion of Subjects Achieving Complete Clearance of EGW by a Given Week (Studies EGW1 and EGW2)

Of the 113 ZYCLARA, 3.75%-treated subjects who achieved complete clearance in the two trials, 17 (15%) subjects had a recurrence within 12 weeks.

No trials were conducted directly comparing the 3.75% and 5% concentrations of imiquimod cream in the treatment of external genital warts.

Storage and Handling

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Avoid freezing.

Store ZYCLARA pump bottles upright.