Imiquimod

1 INDICATIONS AND 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 ) • Biopsy-confirmed, primary superficial basal cell carcinoma (sBCC) in immunocompetent adults with a maximum tumor diameter of 2.0 cm on 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. ( 1.2 ) • External genital and perianal warts (EGW) in immunocompetent patients 12 years of age and older. ( 1.3 ) 1.1 Actinic Keratosis Imiquimod Cream is indicated for the topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses (AK) on the face or scalp in immunocompetent adults. 1.2 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 2.0 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. Establish the histological diagnosis of superficial basal cell carcinoma prior to treatment. The safety and effectiveness of Imiquimod Cream have not been established for other types of basal cell carcinomas (BCC), including nodular and morpheaform (fibrosing or sclerosing) types. 1.3 External Genital Warts Imiquimod Cream is indicated for the topical treatment of external genital and perianal warts (EGW) in immunocompetent patients 12 years of age and older.

2 DOSAGE AND ADMINISTRATION • For topical use only; not for oral, ophthalmic, intra-anal or intravaginal use. ( 2.1 ) • AK: Apply once daily before bedtime 2 times per week for a full 16 weeks to a contiguous area of approximately 25 cm 2 on the face or scalp. Apply no more than 1 packet at each application. ( 2.2 ) • sBCC: Apply once daily before bedtime 5 times per week for a full 6 weeks to a target tumor with 2 cm maximum diameter on the trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet). Amount of Imiquimod Cream used based on target tumor diameter. ( 2.3 ) • EGW: Apply thin layer once daily before bedtime 3 times per week until total clearance or for a maximum of 16 weeks. ( 2.4 ) 2.1 Important Dosage and Administration Instructions Imiquimod Cream is for topical use only. Imiquimod Cream is not for oral, ophthalmic, or intravaginal use. Instruct patients on proper application technique. Wash hands before and after applying Imiquimod Cream. Wash the treatment area with mild soap and water and allow the area to dry thoroughly (at least 10 minutes) before applying Imiquimod Cream. If an Imiquimod Cream 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. For patients with AK and sBCC, prescribe no more than 3 boxes (36 packets) of Imiquimod Cream for the entire treatment period. For EGW, one packet of Imiquimod Cream contains sufficient cream to cover a wart area of up to 20 cm 2 . Discard partially used packets and do not reuse. 2.2 Dosage and Administration for Actinic Keratosis Apply Imiquimod Cream topically once daily before bedtime 2 times per week for a full 16 weeks to a defined treatment area of AK on the face or scalp (but not both concurrently). A treatment area is defined as one contiguous area of approximately 25 cm 2 (e.g., 5 cm × 5 cm) on the face (e.g., forehead or one cheek) or on the scalp. Apply Imiquimod Cream to the entire treatment area and rub in until the cream is no longer visible. Apply no more than 1 packet of Imiquimod Cream to the contiguous treatment area at each application. Leave Imiquimod Cream 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 [see Warnings and Precautions ( 5.1 )] . Do not extend treatment beyond 16 weeks due to missed doses or rest periods. Assess response to treatment after resolution of local skin reactions. 2.3 Dosage and Administration for Superficial Basal Cell Carcinoma Apply Imiquimod Cream topically once daily before bedtime 5 times per week for a full 6 weeks to a biopsy-confirmed sBCC. 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 amount of cream needed to cover the target tumor, including 1 cm of skin surrounding the tumor, is presented in Table 1. Rub Imiquimod Cream into the treatment area until the cream is no longer visible. Leave Imiquimod Cream on the skin for approximately 8 hours and then remove with mild soap and water. Table 1: Amount of Imiquimod Cream to Use for sBCC Target Tumor Diameter Size of Cream Droplet to be Used (Diameter) Approximate Amount of Imiquimod Cream to be Used 0.5 to <1.0 cm 4 mm 10 mg ≥1.0 to <1.5 cm 5 mm 25 mg ≥1.5 to 2.0 cm 7 mm 40 mg 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 [see Warnings and Precautions ( 5.1 )] . Assess for early clinical clearance after resolution of local skin reactions (e.g., 12 weeks post-treatment). Local skin reactions or other findings (e.g., infection) may require that a patient be seen sooner than the post-treatment assessment for clinical clearance. If there is clin…

5 WARNINGS AND PRECAUTIONS • Local Skin Reactions: Intense local inflammatory reactions can occur (e.g., skin weeping, erosion) Dosage interruption may be required. Severe vulvar swelling may occur and lead to urinary retention; interrupt dosing or discontinue for severe vulvar swelling. ( 5.1 ) • Local Hypopigmentation Reactions: Localized complete depigmentation has occurred and persisted. Discontinue if hypopigmentation develops. ( 5.2 ) • Systemic Reactions: Flu-like systemic signs and symptoms have occurred. Consider dosage interruption for systemic reactions. ( 5.3 ) • Ultraviolet Light Exposure Risks: Avoid or minimize exposure to sunlight and sunlamps. Wear sunscreen and protective clothing. ( 5.4 ) 5.1 Local Skin Reactions Local skin reactions including skin weeping or erosion have been reported with Imiquimod Cream and can occur after a few applications [see Adverse Reactions ( 6.1 )] . Concomitant use of Imiquimod Cream and any other imiquimod products, in the same treatment area, may increase the risk for and severity of local skin reactions. Imiquimod 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 urinary retention. Avoid sexual (genital, anal, oral) contact while Imiquimod Cream is on the skin. To reduce the risk of local skin reactions and manage local skin reactions that occur with Imiquimod Cream treatment: • Avoid concomitant use of Imiquimod Cream with any other imiquimod product in the same treatment area. • Avoid application of Imiquimod Cream 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 , 2.4 )] . Interrupt dosing or discontinue Imiquimod Cream for severe vulvar swelling [see Dosage and Administration ( 2.4 )] . • If severe local skin reactions occur, instruct patients to remove Imiquimod Cream by washing the treatment area with mild soap and water. 5.2 Local Hypopigmentation Reactions Cases of hypopigmentation, including complete depigmentation, were reported during postmarketing use of Imiquimod Cream. In some cases, hypopigmentation and complete depigmentation did not improve or resolve with treatment and persisted for up to 60 months at the time of reporting. Discontinue Imiquimod Cream if hypopigmentation develops. 5.3 Systemic Reactions Flu-like signs and symptoms have been reported with use of Imiquimod Cream and may accompany, or even precede, local inflammatory reactions [see Adverse Reactions ( 6.1 )] . Signs and symptoms may include malaise, fever, nausea, myalgias, and rigors. Concomitant use of Imiquimod Cream and any other imiquimod products may increase the risk for and severity of systemic reactions. Consider an interruption of dosing if systemic reactions occur. 5.4 Ultraviolet Light Exposure Risks Imiquimod Cream may cause heightened sunburn susceptibility. Avoid or minimize exposure to sunlight (including sunlamps) during use of Imiquimod Cream. Instruct patients to use sunscreen and wear protective clothing (e.g., a hat). Advise patients not to use Imiquimod Cream until fully recovered from a sunburn.

4 CONTRAINDICATIONS None. None. ( 4 )

8.1 Pregnancy Risk Summary Available data from case reports and case series of use with imiquimod during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. 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 98 times and 407 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 defect, loss, or 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 2 packets per treatment of Imiquimod Cream (25 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 (577 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 (98 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 (1.5 times the MRHD based on BSA comparison), the highest dose evaluated in this study, or 1 mg/kg/day (407 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 (87 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 (87 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 (41 times the MRHD based on AUC comparison).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Local Skin Reactions [see Warnings and Precautions ( 5.1 )] • Local Hypopigmentation Reactions [see Warnings and Precautions ( 5.2 )] • Systemic Reactions [see Warnings and Precautions ( 5.3 )] Most common application site or local skin adverse reactions (incidence >28%) are erythema, flaking/scaling/dryness, scabbing/crusting, edema, erosion/ulceration, induration, itching, burning, excoriation, vesicles. Other reported systemic adverse reactions (≥1%): fatigue, fever, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Padagis ® at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Imiquimod Cream or vehicle in 436 subjects with AK enrolled in two double-blind, vehicle-controlled trials (Studies AK1 and AK2) [see Clinical Studies (14.1)] . Subjects applied Imiquimod Cream, 5% or vehicle topically, to a 25 cm 2 contiguous treatment area on the face or scalp once daily 2 times per week for 16 weeks. The incidence of selected adverse reactions reported by ≥1% of subjects during the trials is presented in Table 2. Table 2: Selected Adverse Reactions Occurring in ≥1% of Imiquimod-Treated Subjects with AK and at a Greater Frequency than Vehicle in Studies AK1 and AK2 Imiquimod Cream (n= 215) Vehicle (n= 221) Application Site Reaction 71 (33%) 32 (14%) Upper Respiratory 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%) The incidence of application site reactions reported by >1% of subjects during the trials is presented in Table 3. Table 3: Application Site Reactions Reported by >1% of Imiquimod-Treated Subjects with AK and at a Greater Frequency than Vehicle in Studies AK1 and AK2 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". The incidence and severity of local skin reactions that occurred during controlled trials are shown in Table 4. Table 4: Local Skin Reactions in the Treatment Area of Imiquimod-Treated Subjects with AK as Assessed by the Investigator in Studies AK1 and AK2 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 trial) were local skin and application site reactions. In the trials, 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 had at least one rest period. Of the imiquimod-treated subjects, 32 (91%) resumed therapy after a rest period. In the AK …