IMIQUIMOD

Imiquimod Cream USP, 5% is an immune response modifier for topical administration. Each gram contains 50 mg of imiquimod 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 is 1-(2-methylpropyl)-1 H -imidazo[4,5-c]quinolin-4-amine. Imiquimod has a molecular formula of C 14 H 16 N 4 and a molecular weight of 240.3. Its structural formula is: Chemical Structure

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.

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.

None. None ( 4 )

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%) 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 Mild, Moderate, or Severe 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%) 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. 6.2 Clinical Trials Experience: Superficial Basal Cell Carcinoma The data described below reflect exposure to Imiquimod Cream or vehicle in 364 subjects enrolled in two double-blind, vehicle-controlled studies. Subjects applied Imiquimod Cream or vehicle 5 times per week for 6 weeks. The incidence of adverse reactions reported by > 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%) Upper Resp 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 including erythema, edema, induration, erosion, flaking/scaling, scabbing/crusting, itching and burning at the application site. The incidence of application site reactions reported by > 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 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 studies, 2% (4/185) of subjects discontinued for local skin/application site reactions. In the sBCC studies, 17 of 1266 (1.3%) Imiquimod -treated subjects developed treatment site infections that required a rest period and treatment with antibiotics. 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 the following table. Table 8: Local Skin Reactions in the Treatment Area as Assessed by the Investigator (External Genital Warts) Imiquimod Cream Vehicle Females Males Females Males (n=114) (n=156) (n=99) (n=157) All Grades Mild, Moderate, or Severe 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%) 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 Incidences reported without regard to causality with Imiquimod Cream. 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%) 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-Schonlein purpura syndrome

Store at 4° to 25°C (39° to 77°F) Avoid freezing. Keep out of reach of children.