Data from FDA - Curated by Toby Galbraith - Last updated 19 April 2017

Indication(s)

1 INDICATIONS AND USAGE •ZYCLARA Cream, 2.5% and 3.75% are indicated for the topical treatment of clinically typical, visible or palpable actinic keratoses (AK) of the full face or balding scalp in immunocompetent adults. (1.1) •ZYCLARA Cream, 3.75% is also indicated for the topical treatment of external genital and perianal warts/condyloma acuminata (EGW) in patients 12 years or older. (1.2) •Limitations of Use: Efficacy of imiquimod cream was not demonstrated for molluscum contagiosum in children 2 to 12 years of age. (1.3, 8.4) 1.1 Actinic Keratosis ZYCLARA Cream, 2.5% and 3.75% are indicated for the topical treatment of clinically typical visible or palpable, actinic keratoses (AK), of the full face or balding scalp in immunocompetent adults. 1.2 External Genital Warts ZYCLARA Cream, 3.75% is indicated for the treatment of external genital and perianal warts (EGW)/condyloma acuminata in patients 12 years or older. 1.3 Limitations of Use Imiquimod cream has been evaluated in children ages 2 to 12 years with molluscum contagiosum and these studies failed to demonstrate efficacy [see Use in Specific Populations (8.4)]. Treatment with ZYCLARA Cream has not been studied for prevention or transmission of HPV. 1.4 Unevaluated Populations The safety and efficacy of ZYCLARA Cream have not been established in the treatment of: •urethral, intravaginal, cervical, rectal or intra-anal human papilloma viral disease. •actinic keratosis when treated with more than one 2-cycle treatment course in the same area. •patients with xeroderma pigmentosum. •superficial basal cell carcinoma. •immunosuppressed patients.

Learning Zones

An epgonline.org Learning Zone (LZ) is an area of the site dedicated to providing detailed self-directed medical education about a disease, condition or procedure.

Airway Disease

The Airway Disease Learning Zone is an area where you can access the information about VisionAir and the upcoming live broadcast. A video presentation will be available from EAACI 2017 entitled 'Personalising Clinical Management in Severe Asthma'. The Inhalation Technology page will feature video presentations from the live broadcast soon. 

Visit Airway Disease


Bedwetting

Essential screening, diagnosis and best strategies to manage bedwetting

Visit Bedwetting


Related Content

Advisory information

contraindications
4 CONTRAINDICATIONS None. •None. (4)
Adverse reactions
6 ADVERSE REACTIONS 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. Most common adverse reactions (>4%) are local skin reactions (erythema, edema, erosion/ulceration, exudate, scabbing/crusting), headache, application site pain, application site irritation, application site pruritus, fatigue, influenza-like illness, and nausea. (6.1, 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience: Actinic Keratosis The data described below reflect exposure to ZYCLARA Cream or vehicle in 479 subjects enrolled in two double-blind, vehicle-controlled trials. Subjects applied up to two packets of ZYCLARA Cream or vehicle 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. Table 1: Selected Adverse Reactions Occurring in ≥2% of ZYCLARA-Treated Subjects and at a Greater Frequency than with Vehicle in the Combined Studies (AK) Adverse Reactions ZYCLARA Cream, 3.75% (N=160) ZYCLARA Cream, 2.5% (N=160) Vehicle (N=159) Headache 10 (6%) 3 (2%) 5 (3%) Application site pruritus 7 (4%) 6 (4%) 1 (<1%) Fatigue 7 (4%) 2 (1%) 0 Nausea 6 (4%) 1 (1%) 2 (1%) Influenza-like illness 1 (<1%) 6 (4%) 0 Application site irritation 5 (3%) 4 (3%) 0 Pyrexia 5 (3%) 0 0 Anorexia 4 (3%) 0 0 Dizziness 4 (3%) 1 (<1%) 0 Herpes simplex 4 (3%) 0 1 (<1%) Application site pain 5 (3%) 2 (1%) 0 Lymphadenopathy 3 (2%) 4 (3%) 0 Oral herpes 0 4 (3%) 0 Arthralgia 2 (1%) 4 (3%) 0 Cheilitis 0 3 (2%) 0 Diarrhea 3 (2%) 2 (1%) 0 Local skin reactions were recorded as adverse reactions only if they extended beyond the treatment area, if they required any medical intervention, or they resulted in patient discontinuation from the study. The incidence and severity of selected local skin reactions are shown in Table 2. Table 2: Local Skin Reactions in the Treatment Area in ZYCLARA-Treated Subjects as Assessed by the Investigator (AK) All Grades Mild, moderate or severe (%) Severe (%) ZYCLARA Cream, 3.75% (N=160) ZYCLARA Cream, 2.5% (N=160) Vehicle (N=159) Erythema Severe erythema 96% 25% 96% 14% 78% 0% Scabbing/Crusting Severe scabbing/crusting 93% 14% 84% 9% 45% 0% Edema Severe edema 75% 6% 63% 4% 19% 0% Erosion/Ulceration Severe erosion/ulceration 62% 11% 52% 9% 9% 0% Exudate Severe exudate 51% 6% 39% 1% 4% 0% Flaking/Scaling/Dryness Severe flaking/scaling/dryness 91% 8% 88% 4% 77% 1% Overall, in the clinical trials, 11% (17/160) of subjects in the ZYCLARA Cream, 3.75% arm, 7% (11/160) of subjects in the ZYCLARA Cream, 2.5% arm, and 0% in the vehicle cream arm required rest periods due to adverse local skin reactions. Other adverse reactions observed in subjects treated with ZYCLARA Cream include: application site bleeding, application site swelling, chills, dermatitis, herpes zoster, insomnia, lethargy, myalgia, pancytopenia, pruritus, squamous cell carcinoma, and vomiting. 6.2 Clinical Trials Experience: External Genital Warts In two double-blind, placebo-controlled studies, 602 subjects applied up to one packet of ZYCLARA Cream or vehicle daily for up to 8 weeks. The most frequently reported adverse reactions were application site reactions and local skin reactions. Selected adverse reactions are listed in Table 3. Table 3: Selected Adverse Reactions Occurring in ≥ 2% of ZYCLARA-Treated Subjects and at a Greater Frequency than with Vehicle in the Combined Trials (EGW) Preferred Term ZYCLARA Cream, 3.75% (N=400) Vehicle Cream (N=202) Application site pain 28 (7%) 1 (<1%) Application site irritation 24 (6%) 2 (1%) Application site pruritus 11 (3%) 2 (1%) Vaginitis bacterialpercentage based on female population of 6/216 for ZYCLARA Cream 3.75% and 2/106 for vehicle cream 6 (3%) 2 (2%) Headache 6 (2%) 1 (<1%) Local skin reactions were recorded as adverse reactions only if they extended beyond the treatment area, if they required any medical intervention, or they resulted in patient discontinuation from the study. The incidence and severity of selected local skin reactions are shown in Table 4. Table 4: Selected Local Skin Reactions in the Treatment Area Assessed by the Investigator (EGW) All Grades Mild, Moderate, or Severe (%) Severe (%) ZYCLARA Cream, 3.75% (N=400) Vehicle Cream (N=202) Erythema Severe erythema 70% 9% 27% <1% Edema Severe edema 41% 2% 8% 0% Erosion/ulceration Severe erosion/ulceration 36% 11% 4% <1% Exudate Severe exudate 34% 2% 2% 0% The frequency and severity of local skin reactions were similar in both genders, with the following exceptions: a) flaking/scaling occurred in 40% of men and in 26% of women and b) scabbing/crusting occurred in 34% of men and in 18% of women. In the clinical trials, 32% (126/400) of subjects who used ZYCLARA Cream and 2% (4/202) of subjects who used vehicle cream discontinued treatment temporarily (required rest periods) due to adverse local skin reactions, and 1% (3/400) of subjects who used ZYCLARA Cream discontinued treatment permanently due to local skin/application site reactions. Other adverse reactions reported in subjects treated with ZYCLARA Cream include: 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. 6.3 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-Schonlein purpura syndrome

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION For topical use only; ZYCLARA Cream is not for oral, ophthalmic, intra-anal or intravaginal use. •For topical use only; not for oral, ophthalmic, intra-anal or intravaginal use. (2) •Actinic Keratosis: Once daily to the skin of the affected area (either the entire face or balding scalp) for two 2-week treatment cycles separated by a 2-week no-treatment period. (2.1) •External Genital Warts: Once daily to the external genital/perianal warts until total clearance or up to 8 weeks. (2.2) 2.1 Actinic Keratosis ZYCLARA Cream should be applied once daily before bedtime 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. ZYCLARA Cream should be applied as a thin film to the entire treatment area and rubbed in until the cream is no longer visible. Up to 0.5 grams (2 packets or 2 full actuations of the pump) of ZYCLARA Cream may be applied to the treatment area at each application. ZYCLARA Cream should be left on the skin for approximately 8 hours, after which time the cream should be removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of ZYCLARA Cream therapy. Patients should wash their hands before and after applying ZYCLARA Cream. Avoid use in or on the lips and nostrils. Do not use in or near the eyes. Local skin reactions in the treatment area are common [see Adverse Reactions (6.1)]. A rest period of several days may be taken if required by the patient's discomfort or severity of the local skin reaction. However, neither 2-week treatment cycle should be extended due to missed doses or rest periods. A transient increase in lesion counts may be observed during treatment. Response to treatment cannot be adequately assessed until resolution of local skin reactions. The patient should continue dosing as prescribed. Treatment should continue for the full treatment course even if all actinic keratoses appear to be gone. Lesions that do not respond to treatment should be carefully re-evaluated and management reconsidered. Prescribe no more than 2 boxes (56 packets) or two 7.5 g pumps for the total 2-cycle treatment course. Partially-used packets should be discarded and not reused. 2.2 External Genital Warts Patients should apply a thin layer of ZYCLARA Cream once a day to the external genital/perianal warts until total clearance or for up to 8 weeks. Patients should use up to 0.25 grams (one packet or one full actuation of the pump) at each application, which is a sufficient amount of cream to cover the wart area. ZYCLARA Cream should be applied prior to normal sleeping hours and left on the skin for approximately 8 hours, then removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of ZYCLARA Cream therapy. Patients should wash their hands before and after applying ZYCLARA Cream. Local skin reactions at the treatment site are common [see Adverse Reactions (6.2)], and may necessitate a rest period of several days; resume treatment once the reaction subsides. Non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions. Prescribe up to 2 boxes (56 packets) or two 7.5 g pumps for the total treatment course. Use of excessive amounts of cream should be avoided. Partially-used packets should be discarded and not reused. 2.3 Pump Administration ZYCLARA (imiquimod) Cream pumps should be primed before using for the first time by repeatedly depressing the actuator until cream is dispensed. It is not necessary to repeat this priming process during treatment.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 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 (2.1X 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). 8.3 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. 8.4 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. 8.5 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.
Pregnancy and lactation
8.3 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.

More information

Category Value
Authorisation number NDA022483
Agency product number P1QW714R7M
Orphan designation No
Product NDC 99207-276,99207-270,99207-271
Date Last Revised 01-09-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 1248440
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 Cream pumps upright.
Marketing authorisation holder Valeant Pharmaceuticals North America LLC