Data from FDA - Curated by Toby Galbraith - Last updated 12 July 2017

Indication(s)

1 INDICATIONS & USAGE Imiquimod cream is indicated for the topical treatment of: Clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses (AK) on the face or scalp in immunocompetent adults (1.1) External genital and perianal warts/condyloma acuminata in patients 12 years old or older (1.3) Limitations of Use: Efficacy was not demonstrated for molluscum contagiosum in children aged 2-12 (1.4, 8.4) 1.1 Actinic Keratosis Imiquimod cream is indicated for the topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on the face or scalp in immunocompetent adults. 1.3 External Genital Warts Imiquimod cream is indicated for the treatment of external genital and perianal warts/condyloma acuminata in patients 12 years old or older. 1.4 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 )]. 1.5 Unevaluated Populations The safety and efficacy of imiquimod cream in immunosuppressed patients have not been established. Imiquimod cream should be used with caution in patients with pre-existing autoimmune conditions. The efficacy and safety of imiquimod cream have not been established for patients with Basal Cell Nevus Syndrome or Xeroderma Pigmentosum.

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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 (incidence > 28%) are application site reactions or local skin reactions: itching, burning, erythema, flaking/scaling/dryness, scabbing/crusting, edema, induration, excoriation, erosion, ulceration. Other reported reactions (≥ 1%) include fatigue, fever, and headache (6.1, 6.3) To report SUSPECTED ADVERSE REACTIONS, contact IMPAX Laboratories, Inc. at 1-800-934-6729, 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 imiquimod cream or vehicle in 436 subjects enrolled in two double-blind, vehicle-controlled studies. Subjects applied imiquimod cream or vehicle to a 25 cm2 contiguous treatment area on the face or scalp 2 times per week for 16 weeks. Table 2: Selected Adverse Reactions Occurring in > 1% of Imiquimod-Treated Subjects and at a Greater Frequency than with Vehicle in the Combined Studies (Actinic Keratosis ) Preferred Term Imiquimod Cream (n=215) Vehicle (n=221) Application Site Reaction 71 (33%) 32 (14%) Upper Resp Tract Infection 33 (15%) 27 (12%) Sinusitis 16 (7%) 14 (6%) Headache 11 (5%) 7 (3%) Carcinoma Squamous 8 (4%) 5 (2%) Diarrhea 6 (3%) 2 (1%) Eczema 4 (2%) 3 (1%) Back Pain 3 (1%) 2 (1%) Fatigue 3 (1%) 2 (1%) Fibrillation Atrial 3 (1%) 2 (1%) Infection Viral 3 (1%) 2 (1%) Dizziness 3 (1%) 1 (<1%) Vomiting 3 (1%) 1 (<1%) Urinary Tract Infection 3 (1%) 1 (<1%) Fever 3 (1%) 0 (0%) Rigors 3 (1%) 0 (0%) Alopecia 3 (1%) 0 (0%) Table 3: Application Site Reactions Reported by > 1% of Imiquimod-Treated Subjects and at a Greater Frequency than with Vehicle in the Combined Studies (Actinic Keratosis ) Included Term Imiquimod Cream (n=215) Vehicle (n=221) Itching 44 (20%) 17 (8%) Burning 13 (6%) 4 (2%) Bleeding 7 (3%) 1 (<1%) Stinging 6 (3%) 2 (1%) Pain 6 (3%) 2 (1%) Induration 5 (2%) 3 (1%) Tenderness 4 (2%) 3 (1%) Irritation 4 (2%) 0 (0%) Local skin reactions were collected independently of the adverse reaction "application site reaction" in an effort to provide a better picture of the specific types of local reactions that might be seen. The most frequently reported local skin reactions were erythema, flaking/scaling/dryness, and scabbing/crusting. The prevalence and severity of local skin reactions that occurred during controlled studies are shown in the following table. Table 4: Local Skin Reactions in the Treatment Area as Assessed by the Investigator (Actinic Keratosis ) Imiquimod Cream (n=215) Vehicle (n=220) All Grades* Severe All Grades* Severe Erythema 209 (97%) 38 (18%) 206 (93%) 5 (2%) Flaking/Scaling/Dryness 199 (93%) 16 (7%) 199 (91%) 7 (3%) Scabbing/Crusting 169 (79%) 18 (8%) 92 (42%) 4 (2%) Edema 106 (49%) 0 (0%) 22 (10%) 0 (0%) Erosion/Ulceration 103 (48%) 5 (2%) 20 (9%) 0 (0%) Weeping/Exudate 45 (22%) 0 (0%) 3 (1%) 0 (0%) Vesicles 19 (9%) 0 (0%) 2 (1%) 0 (0%) *Mild, Moderate, or Severe The adverse reactions that most frequently resulted in clinical intervention (e.g., rest periods, withdrawal from study) were local skin and application site reactions. Overall, in the clinical studies, 2% (5/215) of subjects discontinued for local skin/application site reactions. Of the 215 subjects treated, 35 subjects (16%) on imiquimod cream and 3 of 220 subjects (1%) on vehicle cream had at least one rest period. Of these imiquimod cream subjects, 32 (91%) resumed therapy after a rest period. In the AK studies, 22 of 678 (3.2%) of imiquimod-treated subjects developed treatment site infections that required a rest period off imiquimod cream and were treated with antibiotics (19 with oral and 3 with topical). Of the 206 imiquimod subjects with both baseline and 8-week post-treatment scarring assessments, 6 (2.9%) had a greater degree of scarring scores at 8-weeks post-treatment than at baseline. 6.3 Clinical Trials Experience: External Genital Warts In controlled clinical trials for genital warts, the most frequently reported adverse reactions were local skin and application site reactions. Some subjects also reported systemic reactions. Overall, 1.2% (4/327) of the subjects discontinued due to local skin/application site reactions. The incidence and severity of local skin reactions during controlled clinical trials are shown in Table 8. Table 8: Local Skin Reactions in the Treatment Area as Assessed by the Investigator (External Genital Warts ) Imiquimod cream Vehicle Females (n=114) Males (n=156) Females (n=99) Males (n=157) All Grades* Severe All Grades* Severe All Grades* Severe All Grades* Severe Erythema 74 (65%) 4 (4%) 90 (58%) 6 (4%) 21 (21%) 0 (0%) 34 (22%) 0 (0%) Erosion 35 (31%) 1 (1%) 47 (30%) 2 (1%) 8 (8%) 0 (0%) 10 (6%) 0 (0%) Excoriation /Flaking 21 (18%) 0 (0%) 40 (26%) 1 (1%) 8 (8%) 0 (0%) 12 (8%) 0 (0%) Edema 20 (18%) 1 (1%) 19 (12%) 0 (0%) 5 (5%) 0 (0%) 1 (1%) 0 (0%) Scabbing 4 (4%) 0 (0%) 20 (13%) 0 (0%) 0 (0%) 0 (0%) 4 (3%) 0 (0%) Induration 6 (5%) 0 (0%) 11 (7%) 0 (0%) 2 (2%) 0 (0%) 3 (2%) 0 (0%) Ulceration 9 (8%) 3 (3%) 7 (4%) 0 (0%) 1 (1%) 0 (0%) 1 (1%) 0 (0%) Vesicles 3 (3%) 0 (0%) 3 (2%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) *Mild, Moderate, or Severe Remote site skin reactions were also reported. The severe remote site skin reactions reported for females were erythema (3%), ulceration (2%), and edema (1%); and for males, erosion (2%), and erythema, edema, induration, and excoriation/flaking (each 1%). Selected adverse reactions judged to be probably or possibly related to imiquimod cream are listed below. Table 9: Selected Treatment Related Reactions (External Genital Warts ) Females Males Imiquimod cream (n=117) Vehicle (n=103) Imiquimod cream (n=156) Vehicle (n=158) Application Site Disorders: Application Site Reactions Wart Site: Itching 38 (32%) 21 (20%) 34 (22%) 16 (10%) Burning 30 (26%) 12 (12%) 14 (9%) 8 (5%) Pain 9 (8%) 2 (2%) 3 (2%) 1 (1%) Soreness 3 (3%) 0 (0%) 0 (0%) 1 (1%) Fungal Infection* 13 (11%) 3 (3%) 3 (2%) 1 (1%) Systemic Reactions: Headache 5 (4%) 3 (3%) 8 (5%) 3 (2%) Influenza-like symptoms 4 (3%) 2 (2%) 2 (1%) 0 (0%) Myalgia 1 (1%) 0 (0%) 2 (1%) 1 (1%) *Incidences reported without regard to causality with imiquimod cream. Adverse reactions judged to be possibly or probably related to imiquimod cream and reported by more than 1% of subjects included: Application Site Disorders: burning, hypopigmentation, irritation, itching, pain, rash, sensitivity, soreness, stinging, tenderness Remote Site Reactions: bleeding, burning, itching, pain, tenderness, tinea cruris Body as a Whole: fatigue, fever, influenza-like symptoms Central and Peripheral Nervous System Disorders: headache Gastro-Intestinal System Disorders: diarrhea Musculo-Skeletal System Disorders: myalgia 6.4 Clinical Trials Experience: Dermal Safety Studies Provocative repeat insult patch test studies involving induction and challenge phases produced no evidence that imiquimod cream causes photoallergenicity or contact sensitization in healthy skin; however, cumulative irritancy testing revealed the potential for imiquimod cream to cause irritation, and application site reactions were reported in the clinical studies [see Adverse Reactions ( 6 )]. 6.5 Postmarketing Experience The following adverse reactions have been identified during post-approval use of imiquimod cream. 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, atrial fibrillation, palpitations), chest pain, ischemia, myocardial infarction, syncope Endocrine: thyroiditis Gastro-Intestinal 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 Musculo-Skeletal System Disorders: arthralgia Neuropsychiatric: agitation, cerebrovascular accident, convulsions (including febrile convulsions), depression, insomnia, multiple sclerosis aggravation, paresis, suicide Respiratory: dyspnea Urinary System Disorders: proteinuria, dysuria, urinary retention Skin and Appendages: exfoliative dermatitis, erythema multiforme, hyperpigmentation, hypertrophic scar Vascular: Henoch-Schönlein purpura syndrome

Usage information

Dosing and administration
2 DOSAGE & ADMINISTRATION The application frequency for imiquimod cream is different for each indication. Imiquimod is not for oral, ophthalmic, or intravaginal use. Imiquimod cream is not for oral, ophthalmic, or intravaginal use. (2) Actinic keratosis: 2 times per week for a full 16 weeks (2.1) External genital warts (EGW): 3 times per week until total clearance or a maximum of 16 weeks (2.3) 2.1 Actinic Keratosis Imiquimod cream should be applied 2 times per week for a full 16 weeks to a defined treatment area on the face or scalp (but not both concurrently). The treatment area is defined as one contiguous area of approximately 25 cm2 (e.g., 5 cm × 5 cm) on the face (e.g., forehead or one cheek) or on the scalp. Examples of 2 times per week application schedules are Monday and Thursday, or Tuesday and Friday. Imiquimod cream should be applied to the entire treatment area and rubbed in until the cream is no longer visible. No more than one packet of imiquimod cream should be applied to the contiguous treatment area at each application. Imiquimod cream should be applied prior to normal sleeping hours and 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 imiquimod cream therapy. It is recommended that patients wash their hands before and after applying imiquimod cream. Before applying the cream, the patient should wash the treatment area with mild soap and water and allow the area to dry thoroughly (at least 10 minutes). Contact with the eyes, lips and nostrils should be avoided. Local skin reactions in the treatment area are common [see Adverse Reactions ( 6.1 , 6.5 )]. A rest period of several days may be taken if required by the patient's discomfort or severity of the local skin reaction. However, the treatment period should not be extended beyond 16 weeks due to missed doses or rest periods. Response to treatment cannot be adequately assessed until resolution of local skin reactions. Lesions that do not respond to treatment should be carefully re-evaluated and management reconsidered. Imiquimod cream is packaged in single-use packets, with 24 packets supplied per box. Patients should be prescribed no more than 36 packets for the 16-week treatment period. Unused packets should be discarded. Partially-used packets should be discarded and not reused. 2.3 External Genital Warts Imiquimod cream should be applied 3 times per week to external genital/perianal warts. Imiquimod cream treatment should continue until there is total clearance of the genital/perianal warts or for a maximum of 16 weeks. Examples of 3 times per week application schedules are: Monday, Wednesday, Friday or Tuesday, Thursday, Saturday. Imiquimod cream should be applied prior to normal sleeping hours and left on the skin for 6 -10 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 imiquimod cream therapy. It is recommended that patients wash their hands before and after applying imiquimod cream. A thin layer of imiquimod cream should be applied to the wart area and rubbed in until the cream is no longer visible. The application site should not be occluded. Following the treatment period the cream should be removed by washing the treated area with mild soap and water. Local skin reactions at the treatment site are common [see Adverse Reactions ( 6.3 , 6.5 )]. A rest period of several days may be taken if required by the patient's discomfort or severity of the local skin reaction. Treatment may resume once the reaction subsides. Non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions. Imiquimod cream is packaged in single-use packets which contain sufficient cream to cover a wart area of up to 20 cm2; use of excessive amounts of cream should be avoided.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: Note: The Maximum Recommended Human Dose (MRHD) was set at 2 packets per treatment of imiquimod cream (25 mg imiquimod) for the animal multiple of human exposure ratios presented in this label. If higher doses than 2 packets of imiquimod cream are used clinically, then the animal multiple of human exposure would be reduced for that dose. A non-proportional increase in systemic exposure with increased dose of imiquimod cream was noted in the clinical pharmacokinetic study conducted in actinic keratosis subjects [see Clinical Pharmacology ( 12.3 )]. The AUC after topical application of 6 packets of imiquimod cream was 8 fold greater than the AUC after topical application of 2 packets of imiquimod cream in actinic keratosis subjects. Therefore, if a dose of 6 packets per treatment of imiquimod cream was topically administered to an individual, then the animal multiple of human exposure would be either 1/3 of the value provided in the label (based on body surface area comparisons) or 1/8 of the value provided in the label (based on AUC comparisons). The animal multiples of human exposure calculations were based on weekly dose comparisons for the carcinogenicity studies described in this label. The animal multiples of human exposure calculations were based on daily dose comparisons for the reproductive toxicology studies described 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 (gestational days 6-15) to pregnant female rats. In the presence of maternal toxicity, fetal effects noted at 20 mg/kg/day (577× 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 (98× 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 (1.5× MRHD based on BSA comparisons), the highest dose evaluated in this study, or 1 mg/kg/day (407× 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 (87× 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 (87× 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 (41× MRHD based on AUC comparisons). There are no adequate and well-controlled studies in pregnant women. Imiquimod cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether imiquimod is excreted in human milk following use of imiquimod cream. Because many drugs are excreted in human milk, caution should be exercised when imiquimod cream is administered to nursing women. 8.4 Pediatric Use AK is not a condition generally seen within the pediatric population. The safety and efficacy of imiquimod cream for AK in patients less than 18 years of age have not been established. Safety and efficacy in patients with external genital/perianal warts below the age of 12 years have not been established. Imiquimod 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 215 subjects treated with imiquimod cream in the AK clinical studies, 127 subjects (59%) were 65 years and older, while 60 subjects (28%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. No other clinical experience has identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

More information

Category Value
Authorisation number ANDA091044
Agency product number P1QW714R7M
Orphan designation No
Product NDC 0115-1476
Date Last Revised 26-06-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 310982
Marketing authorisation holder Impax Generics