Imiquimod

Warnings and Precautions, Local Hypopigmentation Reactions ( 5.2 ) 09/2024

1 INDICATIONS AND USAGE Imiquimod Cream USP, 5% is indicated for the topical treatment of: Clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses (AK) on the face or scalp in immunocompetent adults ( 1.1 ). Biopsy-confirmed, primary superficial basal cell carcinoma (sBCC) in immunocompetent adults; maximum tumor diameter of 2.0 cm on trunk, neck, or extremities (excluding hands and feet), only when surgical methods are medically less appropriate and patient follow-up can be reasonably assured ( 1.2 ). 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 USP, 5% is indicated for the topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on the face or scalp in immunocompetent adults. 1.2 Superficial Basal Cell Carcinoma Imiquimod Cream is indicated for the topical treatment of biopsy-confirmed, primary superficial basal cell carcinoma (sBCC) in immunocompetent adults, with a maximum tumor diameter of 2 cm, located on the trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet), only when surgical methods are medically less appropriate and patient follow-up can be reasonably assured. The histological diagnosis of superficial basal cell carcinoma should be established prior to treatment, since safety and efficacy of imiquimod cream have not been established for other types of basal cell carcinomas, including nodular and morpheaform (fibrosing or sclerosing) types. 1.3 External Genital Warts Imiquimod Cream USP, 5% 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 USP, 5% 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 USP, 5% 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.

2 DOSAGE AND ADMINISTRATION The application frequency for Imiquimod Cream is different for each indication. Imiquimod Cream 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 ) • Superficial basal cell carcinoma: 5 times per week for a full 6 weeks ( 2.2 ) • 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 cm 2 (e.g., 5 cm x 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 12 or 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. 2.2 Superficial Basal Cell Carcinoma Imiquimod Cream should be applied 5 times per week for a full 6 weeks to a biopsy-confirmed superficial basal cell carcinoma. An example of a 5 times per week application schedule is to apply Imiquimod Cream, once per day, Monday through Friday. 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. The patient should wash the treatment area with mild soap and water before applying the cream, and allow the area to dry thoroughly. The target tumor should have a maximum diameter of 2 cm and be located on the trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet). The treatment area should include a 1 cm margin of skin around the tumor. Sufficient cream should be applied to cover the treatment area, including 1 centimeter of skin surrounding the tumor. Imiquimod Cream should be rubbed into the treatment area until the cream is no longer visible. TABLE 1. Amount of Imiquimod Cream to Use for sBCC Target Tumor Diameter Size of Cream Droplet to be Used (diameter) Approximate Amount of Imiquim …

3 DOSAGE FORMS AND STRENGTHS Imiquimod Cream, 5%, is supplied in single-use packets each of which contains 250 mg of the cream, equivalent to 12.5 mg of imiquimod. Imiquimod Cream is supplied in boxes of 12 or 24 packets each. • Imiquimod Cream, 5%, is supplied in single-use packets (12 or 24 per box), each of which contains 250 mg of the cream, equivalent to 12.5 mg of imiquimod. ( 3 )

4 CONTRAINDICATIONS None. • None ( 4 )

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, 6.2 , 6.3 ). To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc., at 1-866-923-4914 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 cm 2 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% 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% of subjects during the studies is summarized below. Table 5: Selected Adverse Reactions Reported by > 1% of Imiquimod -Treated Subjects and at a Greater Frequency than with Vehicle in the Combined Studies (Superficial Basal Cell Carcinoma) Imiquimod Cream Vehicle (n= 185) (n= 179) Preferred Term N % N % Application Site Reaction 52 (28%) 5 (3%) Headache 14 (8%) 4 (2%) Back Pain 7 (4%) 1 ( 1% of the subjects during the 6 week treatment period is summarized in the table below. Table 6: Application Site Reactions Reported by > 1% of Imiquimod -Treated Subjects and at a Greater Frequency than with Vehicle in the Combined Studies (Superficial Basal Cell Carcinoma) Imiquimod Cream Vehicle Included Term n=185 n=179 Itching 30 (16%) 1 (1%) Burning 11 (6%) 2 (1%) Pain 6 (3%) 0 (0%) Bleeding 4 (2%) 0 (0%) Erythema 3 (2%) 0 (0%) Papule(s) 3 (2%) 0 (0%) Tenderness 2 (1%) 0 (0%) Infection 2 (1%) 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 prevalence and severity of local skin reactions that occurred during controlled studies are shown in the following table. Table 7: Local Skin Reactions in the Treatment Area as Assessed by the Investigator (Superficial Basal Cell Carcinoma) Imiquimod Cream n=184 Vehicle n=178 All Grades Mild, Moderate, or Severe Severe All Grades Severe Erythema 184 (100%) 57 (31%) 173 (97%) 4 (2%) Flaking/Scaling 167 (91%) 7 (4%) 135 (76%) 0 (0%) Induration 154 (84%) 11 (6%) 94 (53%) 0 (0%) Scabbing/Crusting 152 (83%) 35 (19%) 61 (34%) 0 (0%) Edema 143 (78%) 13 (7%) 64 (36%) 0 (0%) Erosion 122 (66%) 23 (13%) 25 (14%) 0 (0%) Ulceration 73 (40%) 11 (6%) 6 (3%) 0 (0%) Vesicles 57 (31%) 3 (2%) 4 (2%) 0 (0%) The adverse reactions that most frequently resulted in clinical intervention (e.g., rest periods, withdrawal from study) were local skin and application site reactions; 10% (19/185) of subjects received rest periods. The average number of doses not received per subject due to rest perio …

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 (577X 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 (98X 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 (1.5X MRHD based on BSA comparisons), the highest dose evaluated in this study, or 1 mg/kg/day (407X 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 (87X 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 (87X 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 (41X 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 and sBCC are not conditions generally seen within the pediatric population. The safety and efficacy of Imiquimod Cream for AK or sBCC in patients less than 18 years of age ha …

12.1 Mechanism of Action The mechanism of action of Imiquimod Cream in treating AK, sBCC, and EGW lesions is unknown.

11 DESCRIPTION Imiquimod cream USP is an immune response modifier for topical administration. Each gram contains 50 mg of imiquimod, USP in an off-white oil-in-water vanishing cream base consisting of benzyl alcohol, cetyl alcohol, glycerin, isostearic acid, methylparaben, polysorbate 60, propylparaben, purified water, sorbitan monostearate, stearyl alcohol, white petrolatum and xanthan gum. Chemically, imiquimod, USP is 1-(2-methylpropyl)-1 H-imidazo[4,5-c]quinolin-4-amine. Imiquimod, USP has a molecular formula of C 14 H 16 N 4 and a molecular weight of 240.3 g/mol. Its structural formula is: structure.jpg

10 OVERDOSAGE Topical overdosing of Imiquimod Cream could result in an increased incidence of severe local skin reactions and may increase the risk for systemic reactions. Hypotension was reported in a clinical trial following multiple oral imiquimod doses of >200 mg (equivalent to ingestion of the imiquimod content of more than 21 packets or pump actuations of Imiquimod Cream, 3.75% or more than 32 pump actuations of Imiquimod Cream, 2.5%). The hypotension resolved following oral or intravenous fluid administration. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING Imiquimod cream is white to slightly yellow in color. Imiquimod cream USP, 3.75%, is supplied as white plastic 30 mL pump bottle, equipped with a white cap. The 7.5 g pump delivers no fewer than 28 full actuations. 3.75% cream, NDC 51672-4174-9 Imiquimod cream USP, 3.75%, is also supplied in unit-dose foil packets which contain 0.25 g of cream: 3.75% cream, box of 28 packets, NDC 51672-4174-6 Store at 20° to 25°C (68° to 77°F); [see USP Controlled Room Temperature]. Avoid freezing Store imiquimod cream pump bottles upright.