Aldara (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.

The histological diagnosis of basal cell carcinoma should be established prior to treatment, since safety and efficacy of Aldara (Imiquimod) Cream have not been established for other types of basal cell carcinomas, including nodular and morpheaform (fibrosing or sclerosing) types.

The safety and efficacy of Aldara (Imiquimod) Cream in immunosuppressed patients have not been established.

Aldara (Imiquimod) Cream should be used with caution in patients with pre-existing autoimmune conditions.

The efficacy and safety of Aldara (Imiquimod) Cream have not been established for patients with Basal Cell Nevus Syndrome or Xeroderma Pigmentosum.

Aldara (Imiquimod) is not for oral, ophthalmic, or intravaginal use.

Aldara (Imiquimod) Cream, 5%, is supplied in single-use packets each of which contains 250 mg of the cream, equivalent to 12.5 mg of imiquimod. Aldara (Imiquimod) Cream is supplied in boxes of 12 packets each.

None.

Intense local inflammatory reactions including skin weeping or erosion can occur after few applications of Aldara (Imiquimod) Cream and may require an interruption of dosing . Aldara (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 Aldara (Imiquimod) Cream is not recommended until the skin is completely healed from any previous drug or surgical treatment.

Exposure to sunlight (including sunlamps) should be avoided or minimized during use of Aldara (Imiquimod) Cream because of concern for heightened sunburn susceptibility. Patients should be warned to use protective clothing (e.g., a hat) when using Aldara (Imiquimod) Cream. Patients with sunburn should be advised not to use Aldara (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 Aldara (Imiquimod) Cream.

Aldara (Imiquimod) Cream shortened the time to skin tumor formation in an animal photoco-carcinogenicity study . The enhancement of ultraviolet carcinogenicity is not necessarily dependent on phototoxic mechanisms. Therefore, patients should minimize or avoid natural or artificial sunlight exposure.

Safety and efficacy have not been established for Aldara (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 Aldara (Imiquimod) Cream applied to areas of skin greater than 25 cm (e.g. 5 cm × 5 cm) for the treatment of actinic keratosis has not been established .

The safety and efficacy of Aldara (Imiquimod) Cream have not been established for other types of basal cell carcinomas (BCC), including nodular and morpheaform (fibrosing or sclerosing) types. . Patients with sBCC treated with Aldara (Imiquimod) Cream should have regular follow-up of the treatment site .

The safety and efficacy of treating sBCC lesions on the face, head and anogenital area have not been established.

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.

The data described below reflect exposure to Aldara (Imiquimod) Cream or vehicle in 436 subjects enrolled in two double-blind, vehicle-controlled studies. Subjects applied Aldara (Imiquimod) Cream or vehicle to a 25 cm contiguous treatment area on the face or scalp 2 times per week for 16 weeks.

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.

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 Aldara (Imiquimod) Cream and 3 of 220 subjects (1%) on vehicle cream had at least one rest period. Of these Aldara (Imiquimod) Cream subjects, 32 (91%) resumed therapy after a rest period.

In the AK studies, 22 of 678 (3.2%) of Aldara (Imiquimod) -treated subjects developed treatment site infections that required a rest period off Aldara (Imiquimod) Cream and were treated with antibiotics (19 with oral and 3 with topical).

Of the 206 Aldara (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.

The data described below reflect exposure to Aldara (Imiquimod) Cream or vehicle in 364 subjects enrolled in two double-blind, vehicle-controlled studies. Subjects applied Aldara (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.

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.

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.

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%) Aldara (Imiquimod) -treated subjects developed treatment site infections that required a rest period and treatment with antibiotics.

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.

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 Aldara (Imiquimod) Cream are listed below.

Adverse reactions judged to be possibly or probably related to Aldara (Imiquimod) Cream and reported by more than 1% of subjects included:

Application Site Disorders:
Remote Site Reactions:
Body as a Whole:
Central and Peripheral Nervous System Disorders:
Gastro-Intestinal System Disorders:
Musculo-Skeletal System Disorders:
The following adverse reactions have been identified during post-approval use of Aldara (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:
Body as a Whole:
Cardiovascular:
Endocrine:
Gastro-Intestinal System Disorders:
Hematological:
Hepatic:
Infections and Infestations:
Musculo-Skeletal System Disorders:
Neuropsychiatric:
Respiratory:
Urinary System Disorders:
Skin and Appendages:
Vascular:

AK and sBCC are not conditions generally seen within the pediatric population. The safety and efficacy of Aldara (Imiquimod) Cream for AK or sBCC in patients less than 18 years of age have not been established.

Safety and efficacy in patients with external genital/perianal warts below the age of 12 years have not been established.

Aldara (Imiquimod) Cream was evaluated in two randomized, vehicle-controlled, double-blind trials involving 702 pediatric subjects with molluscum contagiosum (MC) (470 exposed to Aldara (Imiquimod) ; median age 5 years, range 2–12 years). Subjects applied Aldara (Imiquimod) Cream or vehicle 3 times weekly for up to 16 weeks. Complete clearance (no MC lesions) was assessed at Week 18. In Study 1, the complete clearance rate was 24% (52/217) in the Aldara (Imiquimod) Cream group compared with 26% (28/106) in the vehicle group. In Study 2, the clearance rates were 24% (60/253) in the Aldara (Imiquimod) Cream group compared with 28% (35/126) in the vehicle group. These studies failed to demonstrate efficacy.

Similar to the studies conducted in adults, the most frequently reported adverse reaction from 2 studies in children with molluscum contagiosum was application site reaction. Adverse events which occurred more frequently in Aldara (Imiquimod) -treated subjects compared with vehicle-treated subjects generally resembled those seen in studies in indications approved for adults and also included otitis media (5% Aldara (Imiquimod) vs. 3% vehicle) and conjunctivitis (3% Aldara (Imiquimod) vs. 2% vehicle).

Erythema was the most frequently reported local skin reaction. Severe local skin reactions reported by Aldara (Imiquimod) -treated subjects in the pediatric studies included erythema (28%), edema (8%), scabbing/crusting (5%), flaking/scaling (5%), erosion (2%) and weeping/exudate (2%).

Systemic absorption of imiquimod across the affected skin of 22 subjects aged 2 to 12 years with extensive MC involving at least 10% of the total body surface area was observed after single and multiple doses at a dosing frequency of 3 applications per week for 4 weeks. The investigator determined the dose applied, either 1, 2 or 3 packets per dose, based on the size of the treatment area and the subject's weight. The overall median peak serum drug concentrations at the end of week 4 was between 0.26 and 1.06 ng/mL except in a 2-year old female who was administered 2 packets of study drug per dose, had a C of 9.66 ng/mL after multiple dosing. Children aged 2–5 years received doses of 12.5 mg (one packet) or 25 mg (two packets) of imiquimod and had median multiple-dose peak serum drug levels of approximately 0.2 or 0.5 ng/mL, respectively. Children aged 6–12 years received doses of 12.5 mg, 25 mg, or 37.5 mg (three packets) and had median multiple dose serum drug levels of approximately 0.1, 0.15, or 0.3 ng/mL, respectively. Among the 20 subjects with evaluable laboratory assessments, the median WBC count decreased by 1.4*10/L and the median absolute neutrophil count decreased by 1.42*10/L.

The most clinically serious adverse event reported following multiple oral imiquimod doses of >200 mg (equivalent to imiquimod content of >16 packets) was hypotension, which resolved following oral or intravenous fluid administration.

Aldara (Imiquimod) (imiquimod 5%) Cream 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 isostearic acid, cetyl alcohol, stearyl alcohol, white petrolatum, polysorbate 60, sorbitan monostearate, glycerin, xanthan gum, purified water, benzyl alcohol, methylparaben, and propylparaben.

Chemically, imiquimod is 1-(2-methylpropyl)-1-imidazo[4,5-c]quinolin-4-amine. Imiquimod has a molecular formula of CHN and a molecular weight of 240.3. Its structural formula is:

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.

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.

In two double-blind, vehicle-controlled clinical studies, 436 subjects with AK were randomized to treatment with either Aldara (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 cm contiguous treatment area on either the face or scalp. The 25 cm contiguous treatment area could be of any dimensions e.g., 5 cm × 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 Aldara (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.

Sub-clinical AK lesions may become apparent in the treatment area during treatment with Aldara (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.

In two double-blind, vehicle-controlled clinical studies, 364 subjects with primary sBCC were treated with Aldara (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 cm and a maximum diameter of 2.0 cm (4.0 cm). 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 Aldara (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 following table.

A separate 5-year, open-label study was conducted to assess the recurrence of sBCC treated with Aldara (Imiquimod) Cream applied once daily 5 days per week for 6 weeks. Target tumor inclusion criteria were the same as for the studies described above. At 12-weeks post-treatment, subjects were clinically evaluated for evidence of persistent sBCC (no histological assessment). Subjects with no clinical evidence of sBCC entered the long-term follow-up period. At the 12 week post-treatment assessment, 90% (163/182) of the subjects enrolled had no clinical evidence of sBCC at their target site and 162 subjects entered the long-term follow-up period for up to 5 years. Two year (24 month) follow-up data are available from this study and are presented in the table below:

In a double-blind, placebo-controlled clinical study, 209 otherwise healthy subjects 18 years of age and older with genital/perianal warts were treated with Aldara (Imiquimod) Cream or vehicle control 3 times per week for a maximum of 16 weeks. The median baseline wart area was 69 mm (range 8 to 5525 mm). Subject accountability is shown in the figure below.

*The other subjects were either lost to follow-up or experienced recurrences.

Data on complete clearance are listed in the table below. The median time to complete wart clearance was 10 weeks.

Aldara (Imiquimod) Cream, 5%, is supplied in single-use packets which contain 250 mg of the cream. Available as: box of 12 packets NDC 99207-260-12.

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