Imiquimod 12.5 mg/.25g Cream, 25 g — NDC 72189-084-24 (Billing 72189-0084-24)

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

12.2Pharmacodynamics 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.

12.3Pharmacokinetics 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.

14.1Actinic Keratosis In two double-blind, vehicle-controlled clinical studies, 436 subjects with AK were randomized to treatment with either imiquimod cream or vehicle cream 2 times per week for 16 weeks. The studies enrolled subjects with 4 to 8 clinically typical, visible, discrete, nonhyperkeratotic, nonhypertrophic AK lesions within a 25 cm2 contiguous treatment area on either the face or scalp. The 25 cm2 contiguous treatment area could be of any dimensions e.g., 5 cm x 5 cm, 3 cm by 8.3 cm, 2 cm by 12.5 cm.

Study subjects ranged from 37 to 88 years of age (median 66 years) and 55% had Fitzpatrick skin type I or II. All imiquimod-treated subjects were Caucasians. On a scheduled dosing day, the study cream was applied to the entire treatment area prior to normal sleeping hours and left on for approximately 8 hours.

Twice weekly dosing was continued for a total of 16 weeks. The clinical response of each subject was evaluated 8 weeks after the last scheduled application of study cream. Efficacy was assessed by the complete clearance rate, defined as the proportion of subjects at the 8-week post-treatment visit with no (zero) clinically visible AK lesions in the treatment area.

Complete clearance included clearance of all baseline lesions, as well as any new or sub-clinical AK lesions which appeared during therapy. Complete and partial clearance rates are shown in the table below. The partial clearance rate was defined as the percentage of subjects in whom 75% or more baseline AK lesions were cleared.

Table 11: Clearance Rates (AK) Complete Clearance Rates (100% AK Lesions Cleared) Study Imiquimod Cream Vehicle Study 46% (49/107) 3% (3/110) AK1 Study 44% (48/108) 4% (4/111) AK2 Partial and Complete Clearance Rates (75% or More Baseline AK Lesions Cleared) Study Imiquimod Cream Vehicle Study 60% (64/107) 10% (11/110) AK1 Study 58% (63/108) 14% (15/111) AK2 Sub-clinical AK lesions may become apparent in the treatment area during treatment with imiquimod cream. During the course of treatment, 48% (103/215) of subjects experienced an increase in AK lesions relative to the number present at baseline within the treatment area.

Subjects with an increase in AK lesions had a similar response to those with no increase in AK lesions.

14.2Superficial Basal Cell Carcinoma In two double-blind, vehicle-controlled clinical studies, 364 subjects with primary sBCC were treated with imiquimod cream or vehicle cream 5 times per week for 6 weeks. Target tumors were biopsy-confirmed sBCC and had a minimum area of 0.5 cm2 and a maximum diameter of 2.0 cm (4.0 cm2). Target tumors were not to be located within 1.0 cm of the hairline, or on the anogenital area or on the hands or feet, or to have any atypical features.

The population ranged from 31-89 years of age (median 60 years) and 65% had Fitzpatrick skin type I or II. On a scheduled dosing day, study cream was applied to the target tumor and approximately 1 cm (about 1/3 inch) beyond the target tumor prior to normal sleeping hours, and 5 times per week dosing was continued for a total of 6 weeks. The target tumor area was clinically assessed 12 weeks after the last scheduled application of study cream.

The entire target tumor was then excised and examined histologically for the presence of tumor. Efficacy was assessed by the complete response rate defined as the proportion of subjects with clinical (visual) and histological clearance of the sBCC lesion at 12 weeks post-treatment. Of imiquimod-treated subjects, 6% (11/178) who had both clinical and histological assessments post-treatment, and who appeared to be clinically clear had evidence of tumor on excision of the clinically-clear treatment area.

Data on composite clearance (defined as both clinical and histological clearance) are shown in the table below. Table 12: Composite Clearance Rates at 12 Weeks Post-Treatment for Superficial Basal Cell Carcinoma Study Imiquimod Cream Vehicle Cream Study sBCC1 70% (66/94) 2% (2/89) Study sBCC2 80% (… [Excerpted — this section continues on DailyMed.]

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility In an oral (gavage) rat carcinogenicity study, imiquimod was administered to Wistar rats on a 2X/week (up to 6 mg/kg/day) or daily (3 mg/kg/day) dosing schedule for 24 months. No treatment related tumors were noted in the oral rat carcinogenicity study up to the highest doses tested in this study of 6 mg/kg administered 2X/week in female rats (87X MRHD based on weekly AUC comparisons), 4 mg/kg administered 2X/week in male rats (75X MRHD based on weekly AUC comparisons) or 3 mg/kg administered 7X/week to male and female rats (153X MRHD based on weekly AUC comparisons).

In a dermal mouse carcinogenicity study, imiquimod cream (up to 5 mg/kg/application imiquimod or 0.3% imiquimod cream) was applied to the backs of mice 3X/week for 24 months. A statistically significant increase in the incidence of liver adenomas and carcinomas was noted in high dose male mice compared to control male mice (251X MRHD based on weekly AUC comparisons). An increased number of skin papillomas was observed in vehicle cream control group animals at the treated site only.

The quantitative composition of the vehicle cream used in the dermal mouse carcinogenicity study is the same as the vehicle cream used for imiquimod cream, minus the active moiety (imiquimod). In a 52-week dermal photo-cocarcinogenecity study, the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing (3X/week; 40 weeks of treatment followed by 12 weeks of observation) with concurrent exposure to UV radiation (5 days per week) with the imiquimod cream vehicle alone.

No additional effect on tumor development beyond the vehicle effect was noted with the addition of the active ingredient, imiquimod, to the vehicle cream. Imiquimod revealed no evidence of mutagenic or clastogenic potential based on the results of five in vitro genotoxicity tests (Ames assay, mouse lymphoma L5178Y assay, Chinese hamster ovary cell chromosome aberration assay, human lymphocyte chromosome aberration assay and SHE cell transformation assay) and three in vivo genotoxicity tests (rat and hamster bone marrow cytogenetics assay and a mouse dominant lethal test).

Daily oral administration of imiquimod to rats, throughout mating, gestation, parturition and lactation, demonstrated no effects on growth, fertility or reproduction, at doses up to 87X MRHD based on AUC comparisons.