Imiquimod

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.

DOSAGE AND ADMINISTRATION The application frequency for Imiquimod Cream is different for each indication. Imiquimod is not for oral, ophthalmic, or intravaginal use. Imiquimod Cream USP, 5% 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 × 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. 2.2 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 Imiquimod to be Used 0.5 to < 1 cm 4 mm 10 mg ≥ 1 to < 1.5 cm 5 mm 25 mg ≥ 1.5 to 2 cm 7 mm 40 mg Contact with the eyes, lips and nostrils should be avoided. Local skin reactions in the treatment area are common [see Adverse Reactions (6.2 , 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. Early clinical clearance cannot be adequately assessed until 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 clinical evidence of persistent tumor at the post-treatment assessment for clinical clearance, a biopsy or other alternative intervention should be considered. Lesions that do not respond to therapy should be carefully re-evaluated and management reconsidered; the safety and efficacy of a repeat course of Imiquimod Cream treatment have not been established. If any suspicious lesion arises in the treatment area at any time after a determination of clinical clearance, the patient should seek a medical evaluation [see Clinical Studies (14.2) . 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 6-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 to 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 cm 2 ; use of excessive amounts of cream should be avoided.

WARNINGS AND PRECAUTIONS Intense local inflammatory reactions can occur (e.g., skin weeping, erosion). Dosing interruption may be required ( 2 , 5.1 , 6 ). Severe local inflammatory reactions of the female external genitalia can lead to severe vulvar swelling. Severe vulvar swelling can lead to urinary retention; dosing should be interrupted or discontinued. Flu-like systemic signs and symptoms including malaise, fever, nausea, myalgias and rigors may occur. Dosing interruption may be required ( 2 , 5.2 , 6 ). Avoid exposure to sunlight and sunlamps. Wear sunscreen daily ( 5.3 ). Safety and efficacy have not been established for repeat courses of treatment to the same area for AK ( 5.4 ). Imiquimod Cream is not recommended for treatment of BCC subtypes other than the superficial variant, i.e., sBCC( 5.5 ). Treatment of urethral, intra-vaginal, cervical, rectal or intra-anal viral disease is not recommended ( 5.6 ). Safety and efficacy in immunosuppressed patients have not been established ( 1.5 ). 5.1 Local Inflammatory Reactions Intense local inflammatory reactions including skin weeping or erosion can occur after few applications of Imiquimod Cream and may require an interruption of dosing [see Dosage and Administration (2) and Adverse Reactions (6) ]. 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. Severe vulvar swelling can lead to urinary retention. Dosing should be interrupted or discontinued for severe vulvar swelling. Administration of Imiquimod Cream is not recommended until the skin is completely healed from any previous drug or surgical treatment. 5.2 Systemic Reactions Flu-like signs and symptoms may accompany, or even precede, local inflammatory reactions and may include malaise, fever, nausea, myalgias and rigors. An interruption of dosing should be considered [see Adverse Reactions (6) ]. 5.3 Ultraviolet Light Exposure Exposure to sunlight (including sunlamps) should be avoided or minimized during use of Imiquimod Cream because of concern for heightened sunburn susceptibility. Patients should be warned to use protective clothing (e.g., a hat) when using Imiquimod Cream. Patients with sunburn should be advised not to use Imiquimod Cream until fully recovered. Patients who may have considerable sun exposure, e.g., due to their occupation, and those patients with inherent sensitivity to sunlight should exercise caution when using Imiquimod Cream. Imiquimod Cream shortened the time to skin tumor formation in an animal photoco-carcinogenicity study [see Nonclinical Toxicology (13.1) ] . The enhancement of ultraviolet carcinogenicity is not necessarily dependent on phototoxic mechanisms. Therefore, patients should minimize or avoid natural or artificial sunlight exposure. 5.4 Unevaluated Uses: Actinic Keratosis Safety and efficacy have not been established for Imiquimod Cream in the treatment of actinic keratosis with repeated use, i.e., more than one treatment course, in the same area. The safety of Imiquimod Cream applied to areas of skin greater than 25 2 cm (e.g., 5 cm X 5 cm) for the treatment of actinic keratosis has not been established [see Clinical Pharmacology (12.3) ]. 5.5 Unevaluated Uses: Superficial Basal Cell Carcinoma The safety and efficacy of Imiquimod Cream have not been established for other types of basal cell carcinomas (BCC), including nodular and morpheaform (fibrosing or sclerosing) types. Imiquimod Cream is not recommended for treatment of BCC subtypes other than the superficial variant (i.e., sBCC) . Patients with sBCC treated with Imiquimod Cream should have regular followup of the treatment site [see Clinical Studies (14.2) ]. The safety and efficacy of treating sBCC lesions on the face, head and anogenital area have not been established. 5.6 Unevaluated Uses: External Genital Warts Imiquimod Cream has not been evaluated for the treatment of urethral, intra-vaginal, cervical, rectal, or intra-anal human papilloma viral disease.

CONTRAINDICATIONS None. None. ( 4 )

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 trials, 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-treated 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. Superficial Basal Cell Carcinoma The data described below reflect exposure to imiquimod cream or vehicle in 364 subjects with sBCC enrolled in two double-blind, vehicle-controlled trials (sBCC1 and sBCC2) [see Clinical Studies ( 14.2 )] . Subjects applied imiquimod cream, 5% or vehicle topically 5 times per week for 6 weeks. The incidence of selected adverse reactions reported by ≥1% of subjects during the trials is summarized in Table 5. Table 5: Selected Adverse Reactions Reported by ≥1% of Imiquimod-Treated Subjects with sBCC and at a Greater Frequency than Vehicle in Studies sBCC1 and sBCC2 Imiquimod Cream (n= 185) N % Vehicle (n= 179) N % Application Site Reaction 52 (28%) 5 (3%) Headache 14 (8%) 4 (2%) Back Pain 7 (4%) 1 (<1%) Upper Respiratory Tract Infection 6 (3%) 2 (1%) Rhinitis 5 (3%) 1 (<1%) Lymphadenopathy 5 (3%) 1 (<1%) Fatigue 4 (2%) 2 (1%) Sinusitis 4 (2%) 1 (<1%) Dyspepsia 3 (2%) 2 (1%) Coughing 3 (2%) 1 (<1%) Fever 3 (2%) 0 (0%) Dizziness 2 (1%) 1 (<1%) Anxiety 2 (1%) 1 (<1%) Pharyngitis 2 (1%) 1 (<1%) Chest Pain 2 (1%) 0 (0%) Nausea 2 (1%) 0 (0%) The most frequently reported adverse reactions were local skin and application site reactions. The incidence of application site reactions reported by >1% of the subjects during the 6-week treatment period is summarized in Table 6. Table 6: Application Site Reactions Reported by > 1% of Imiquimod-Treated Subjects with sBCC and at a Greater Frequency than Vehicle in Studies sBCC1 and sBCC2 Imiquimod Cream (n= 185) Vehicle (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”. The incidence and severity of local skin reactions that occurred during the controlled trials are shown in Table 7. Table 7: Local Skin Reactions in the Treatment Area of Imiquimod-Treated Subjects with sBCC as Assessed by the Investigator in Studies sBCC1 and sBCC2 Imiquimod Cream (n= 184) Vehicle (n= 178) All Grades* 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%) *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; 10% (19/185) of imiquimod-treated subjects received rest periods. The average number of doses not received per imiquimod-treated subject due to rest periods was 7 doses with a range of 2 to 22 doses; 79% of subjects (15/19) resumed therapy after a rest period. Overall, in the clinical trials, 2% (4/185) of imiquimod-treated subjects discontinued for local skin/application site reactions. In the sBCC trials, 17 of 1266 (1.3%) imiquimod-treated subjects developed treatment site infections that required a rest period and treatment with antibiotics. External Genital Warts In controlled clinical trials for EGW, including a double-blind, vehicle-controlled clinical trial in 209 adult subjects with EGW (Study EGW1) [see Clinical Studies ( 14.3 )] , imiquimod cream, 5% was applied topically to EGW in 109 subjects. Selected adverse reactions in imiquimod-treated subjects are listed below

Mechanism of Action The mechanism of action of Imiquimod Cream in treating AK and sBCC lesions is unknown. 12.2 Pharmacodynamics Actinic Keratosis In a study of 18 subjects with AK comparing imiquimod cream to vehicle, increases from baseline in week 2 biomarker levels were reported for CD3, CD4, CD8, CD11c, and CD68 for imiquimod cream treated subjects; however, the clinical relevance of these findings is unknown. Superficial Basal Cell Carcinoma An open label study in six subjects with sBCC suggests that treatment with imiquimod cream may increase the infiltration of lymphocytes, dendritic cells, and macrophages into the tumor lesion; however, the clinical significance of these findings is unknown. External Genital Warts Imiquimod has no direct antiviral activity in cell culture. A study in 22 subjects with genital/perianal warts comparing imiquimod cream and vehicle shows that imiquimod cream induces mRNA encoding cytokines including interferon-ɑ at the treatment site. In addition HPVL1 mRNA and HPV DNA are significantly decreased following treatment. However, the clinical relevance of these findings is unknown. 12.3 Pharmacokinetics Systemic absorption of imiquimod across the affected skin of 58 subjects with AK was observed with a dosing frequency of 3 applications per week for 16 weeks. Mean peak serum drug concentrations at the end of week 16 were approximately 0.1, 0.2, and 3.5 ng/mL for the applications to face (12.5 mg imiquimod, 1 single-use packet), scalp (25 mg, 2 packets) and hands/arms (75 mg, 6 packets), respectively. Table 10: Mean Serum Imiquimod Concentration in Adults Following Administration of the Last Topical Dose During Week 16 (Actinic Keratosis) Amount of Imiquimod Cream applied Mean peak serum imiquimod Concentration [Cmax] 12.5 mg (1 packet) 0.1 ng/mL 25 mg (2 packets) 0.2 ng/mL 75 mg (6 packets) 3.5 ng/mL The application surface area was not controlled when more than one packet was used. Dose proportionality was not observed. However it appears that systemic exposure may be more dependent on surface area of application than amount of applied dose. The apparent half-life was approximately 10 times greater with topical dosing than the 2 hour apparent half-life seen following subcutaneous dosing, suggesting prolonged retention of drug in the skin. Mean urinary recoveries of imiquimod and metabolites combined were 0.08 and 0.15% of the applied dose in the group using 75 mg (6 packets) for males and females, respectively following 3 applications per week for 16 weeks. Systemic absorption of imiquimod was observed across the affected skin of 12 subjects with genital/perianal warts, with an average dose of 4.6 mg. Mean peak drug concentration of approximately 0.4 ng/mL was seen during the study. Mean urinary recoveries of imiquimod and metabolites combined over the whole course of treatment, expressed as percent of the estimated applied dose, were 0.11 and 2.41% in the males and females, respectively.