IMIQUIMOD

5.1 Local Inflammatory Reactions Intense local inflammatory reactions including skin weeping or erosion can occur after a few applications of Imiquimod Cream and may require an interruption of dosing. [see DOSAGE ANDADMINISTRATION(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 photo-cocarcinogenecity 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 cm2 (e.g. 5 cm X 5 cm) or 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 thesuperficial variant (i.e., sBCC). Patients with sBCC treated with Imiquimod Cream should have regular follow-up 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.

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. 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. 6.2 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) Preferred Term 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 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) Included Term 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" 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* 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 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 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 Infestation: 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