Aldara Cream, 5% (3M)

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DESCRIPTION

Aldara™ is the brand name for imiquimod which is an immune response modifier. Each gram of the 5% cream 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 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:

CLINICAL PHARMACOLOGY

Pharmacodynamics

Actinic Keratosis

The mechanism of action of Aldara Cream in treating actinic keratosis (AK) lesions is unknown. In a study of 18 patients with AK comparing Aldara Cream to vehicle, increases from baseline in week 2 biomarker levels were reported for CD3, CD4, CD8, CD11c, and CD68 for Aldara Cream treated patients; however, the clinical relevance of these findings is unknown.

Superficial Basal Cell Carcinoma

The mechanism of action of Aldara Cream in treating superficial basal cell carcinoma (sBCC) lesions is unknown. An open label study in six subjects with sBCC suggests that treatment with Aldara 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 patients with genital/perianal warts comparing Aldara Cream and vehicle shows that Aldara Cream induces mRNA encoding cytokines including interferon-(alpha) 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.

Pharmacokinetics

Systemic absorption of imiquimod was observed across the affected skin of 12 patients 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.

Systemic absorption of imiquimod across the affected skin of 58 patients 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.

CLINICAL STUDIES

Actinic Keratosis

In two double-blind, vehicle-controlled clinical studies, 436 patients with actinic keratosis (AK) were treated with Aldara Cream or vehicle cream 2 times per week for 16 weeks. Patients with 4 to 8 clinically typical, visible, discrete, nonhyperkeratotic, nonhypertrophic AK lesions within a 25 cm ² contiguous treatment area on either the face or scalp were enrolled and randomized to active or vehicle treatment. The population studied ranged from 37-88 years of age (median 66 years) and 55% had Fitzpatrick skin type I or II. All imiquimod-treated patients were Caucasians. The 25 cm ² 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, etc. 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. Eight weeks after the patient's last scheduled application of study cream, the clinical response of each patient was evaluated. The primary efficacy variable was the complete clearance rate. Complete clearance (designated below as "clear") was 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 subclinical AK lesions which appeared during therapy. Patient outcomes are shown in the figure below.

Complete and partial clearance rates are shown in the table below. The partial clearance rate was defined as the percentage of patients 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 Cream. During the course of treatment, 48% (103/215) of patients experienced an increase in AK lesions relative to the number present at baseline within the treatment area. Patients with an increase in AK lesions had a similar response to those with no increase in AK lesions.

Of the 206 imiquimod subjects with both baseline and 8-week post-treatment scarring assessments, only 6 (2.9%) had a greater degree of scarring scores at 8-weeks post-treatment than at baseline.

Superficial Basal Cell Carcinoma

In two double-blind, vehicle-controlled clinical studies, 364 patients with primary superficial basal cell carcinoma (sBCC) were treated with Aldara Cream or vehicle cream 5 × /week for 6 weeks. Patients with one biopsy-confirmed sBCC tumor were enrolled and randomized in a 1:1 ratio to active or vehicle treatment. Target tumors were to have a minimum area of 0.5 cm ² and a maximum diameter of 2.0 cm (4.0 cm ² ). Target tumors were not to be located within 1.0 cm of the hairline, eyes, nose, mouth, ears, on the anogenital area or on the hands or feet, or have any atypical features. On a scheduled dosing day, the 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; 5 × /week dosing was continued for a total of 6 weeks. Twelve weeks after the last scheduled application of study cream, the target tumor area was clinically assessed. The entire target tumor was then excised and examined histologically for the presence of tumor.

The primary efficacy variable was the complete response rate defined as the proportion of patients with clinical (visual) and histological clearance of the sBCC lesion at 12 weeks post-treatment. The population ranged from 31-89 years of age (median 60 years) and 65% had Fitzpatrick skin type I or II. Patient outcomes are shown in the figure below.

Of Aldara-treated patients 6% (11/178) who had both clinical and histological assessments post-treatment, and appeared to be clinically clear in Studies C and D 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.

An open-label 5-year study (Study E) is ongoing to assess the recurrence of sBCC treated with Aldara Cream applied once daily 5 days per week for 6 weeks. Target tumor inclusion criteria were the same as for Studies C and D as described above. At 12-weeks post-treatment, patients were clinically (no histological assessment) evaluated for evidence of persistent sBCC. Subjects with no clinical evidence of BCC entered the long-term follow-up period. At the 12 week post-treatment assessment 163/182 (90%) 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:

[See table below]

External Genital Warts

In a double-blind, placebo-controlled clinical study, 209 otherwise healthy patients 18 years of age and older with genital/perianal warts were treated with Aldara Cream or vehicle control 3 × /week for a maximum of 16 weeks. The median baseline wart area was 69 mm ² (range 8 to 5525 mm ² ). Patient accountability is shown in the figure below.

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

[See table below]

INDICATIONS AND USAGE

Aldara Cream is indicated for the topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on the face or scalp in immunocompetent adults.

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

Aldara Cream is indicated for the treatment of external genital and perianal warts/condyloma acuminata in individuals 12 years old and above.

CONTRAINDICATIONS

This drug is contraindicated in individuals with a history of sensitivity reactions to any of its components. It should be discontinued if hypersensitivity to any of its ingredients is noted.

WARNINGS

The diagnosis of sBCC should be confirmed prior to treatment, since safety and effectiveness of Aldara Cream have not been established for other types of basal cell carcinomas, including nodular, morpheaform (fibrosing or sclerosing) types and is not recommended for treatment of BCC subtypes other than the superficial variant (i.e., sBCC). Patients with sBCC treated with Aldara Cream are recommended to have regular follow-up of the treatment site. See table of Estimated Clinical Clearance Rates for Superficial Basal Cell Carcinoma in the CLINICAL STUDIES section.

Aldara Cream has not been evaluated for the treatment of urethral, intra-vaginal, cervical, rectal, or intra-anal human papilloma viral disease and is not recommended for these conditions.

PRECAUTIONS

General

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

Aldara Cream administration is not recommended until the skin is completely healed from any previous drug or surgical treatment.

Aldara Cream has the potential to exacerbate inflammatory conditions of the skin, including chronic graft versus host disease.

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

Intense local inflammatory reactions including skin weeping or erosion can occur after only a few applications of Aldara Cream. Local inflammatory reactions may be accompanied, or even preceded, by flu-like systemic signs and symptoms including malaise, fever, nausea, myalgias and rigors. An interruption of dosing should be considered.

Exposure to sunlight (including sunlamps) should be avoided or minimized during use of Aldara Cream because of concern for heightened sunburn susceptibility. Patients should be warned to use protective clothing (hat) when using Aldara Cream. Patients with sunburn should be advised not to use Aldara 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 Cream. Phototoxicity has not been adequately assessed for Aldara Cream. The enhancement of ultraviolet carcinogenicity is not necessarily dependent on phototoxic mechanisms. Despite the absence of observed phototoxicity in humans (see ADVERSE REACTIONS ), Aldara Cream shortened the time to skin tumor formation in an animal photoco-carcinogenicity study (see Carcinogenesis, Mutagenesis, Impairment of Fertility ). Therefore, it is prudent for patients to minimize or avoid natural or artificial sunlight exposure.

Actinic Keratosis

Safety and efficacy have not been established for Aldara Cream in the treatment of actinic keratosis with repeated use, i.e. more than one treatment course, in the same 25 cm ² area.

The safety of Aldara Cream applied to areas of skin greater than 25 cm ² (e.g. 5 cm × 5 cm) for the treatment of actinic keratosis has not been established ( see CLINICAL PHARMACOLOGY ; Pharmacokinetics section regarding systemic absorption).

Superficial Basal Cell Carcinoma

The safety and efficacy of treating superficial basal cell carcinoma (sBCC) lesions on the face, head and anogenital area have not been established.

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

Information for Patients

General Information

Patients using Aldara Cream should receive the following information and instructions:

1. This medication is to be used as directed by a physician. It is for external use only. Eye contact should be avoided.
2. The treatment area should not be bandaged or otherwise covered or wrapped as to be occlusive.
3. Some reports have been received of localized hypopigmentation and hyperpigmentation following Aldara Cream use. Follow-up information suggests that these skin color changes may be permanent in some patients.

Patients Being Treated for Actinic Keratosis (AK)

1. It is recommended that the treatment area be washed with mild soap and water 8 hours following Aldara Cream application.
2. It is common for patients to experience local skin reactions (can range from mild to severe in intensity) during treatment with Aldara Cream, and these reactions may extend beyond the application site onto the surrounding skin. Skin reactions generally decrease in intensity or resolve after cessation of Aldara Cream therapy. Potential local skin reactions include erythema, edema, vesicles, erosion/ulceration, weeping/exudate, flaking/scaling/dryness, and scabbing/crusting. Most patients using Aldara Cream for the treatment of AK experience erythema, flaking/scaling/dryness and scabbing/crusting at the application site with normal dosing. Patients may also experience application site reactions such as itching and/or burning. Local skin reactions may be of such an intensity that patients may require rest periods from treatment. Treatment with Aldara Cream can be resumed after the skin reaction has subsided, as determined by the physician. Patients should contact their physician promptly if they experience any sign or symptom at the application site that restricts or prohibits their daily activity or makes continued application of the cream difficult.
3. Because of local skin reactions, during treatment and until healed, the treatment area is likely to appear noticeably different from normal skin. The skin surrounding the treatment area may also be affected, but less intensely so.
4. Contact with the eyes, lips and nostrils should be avoided.
5. Use of sunscreen is encouraged, and patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using Aldara Cream.
6. During treatment, sub-clinical AK lesions may become apparent in the treatment area and may subsequently resolve.
7. Partially-used packets should be discarded and not reused.
8. Dosing is twice weekly for the full 16 weeks, unless otherwise directed by the physician. However, the treatment period should not be extended beyond 16 weeks due to missed doses or rest periods.

Patients Being Treated for Superficial Basal Cell Carcinoma (sBCC)

1. It is recommended that the treatment area be washed with mild soap and water 8 hours following Aldara Cream application.
2. Most patients using Aldara Cream for the treatment of sBCC experience erythema, edema, induration, erosion, scabbing/crusting and flaking/scaling at the application site with normal dosing. These local skin reactions generally decrease in intensity or resolve after cessation of Aldara Cream therapy. Patients may also experience application site reactions such as itching and/or burning. Local skin reactions may be of such an intensity that patients may require rest periods from treatment. Treatment with Aldara Cream can be resumed after the skin reaction has subsided, as determined by the physician.
3. During treatment and until healed, affected skin is likely to appear noticeably different from normal skin.
4. It is prudent for patients to minimize or avoid exposure to natural or artificial sunlight.
5. The clinical outcome of therapy can be determined after regeneration of the treated skin, approximately 12 weeks after the end of treatment.
6. Patients should contact their physician if they experience any sign or symptom at the application site that restricts or prohibits their daily activity or makes continued application of the cream difficult.
7. Patients with sBCC treated with Aldara Cream are recommended to have regular follow-up to re-evaluate the treatment site.

Patients Being Treated for External Genital Warts

1. It is recommended that the treatment area be washed with mild soap and water 6-10 hours following Aldara Cream application.
2. It is common for patients to experience local skin reactions such as erythema, erosion, excoriation/flaking, and edema at the site of application or surrounding areas. Most skin reactions are mild to moderate. Severe skin reactions can occur and should be promptly reported to the prescribing physician. Should severe local skin reaction occur, the cream should be removed by washing the treatment area with mild soap and water. Treatment with Aldara Cream can be resumed after the skin reaction has subsided.
3. Sexual (genital, anal, oral) contact should be avoided while the cream is on the skin.
4. Application of Aldara Cream in the vagina is considered internal and should be avoided. Female patients should take special care if applying the cream at the opening of the vagina because local skin reactions on the delicate moist surfaces can result in pain or swelling, and may cause difficulty in passing urine.
5. Uncircumcised males treating warts under the foreskin should retract the foreskin and clean the area daily.
6. Patients should be aware that new warts may develop during therapy, as Aldara Cream is not a cure.
7. The effect of Aldara Cream on the transmission of genital/perianal warts is unknown.
8. Aldara Cream may weaken condoms and vaginal diaphragms, therefore concurrent use is not recommended.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Note: The Maximum Recommended Human Dose (MRHD) was set at 2 packets per treatment of Aldara Cream (25 mg imiquimod) for the animal multiple of human exposure ratios presented in this label. If higher doses than 2 packets of Aldara Cream are used clinically, then the animal multiple of human exposure would be reduced for that dose. A non-proportional increase in systemic exposure with increased dose of Aldara Cream was noted in the clinical pharmacokinetic study conducted in actinic keratosis subjects ( see Pharmacokinetics ). The AUC after topical application of 6 packets of Aldara Cream was 8 fold greater than the AUC after topical application of 2 packets of Aldara Cream in actinic keratosis subjects. Therefore, if a dose of 6 packets per treatment of Aldara Cream was topically administered to an individual, then the animal multiple of human exposure would be either 1/3 of the value provided in the label (based on body surface area comparisons) or 1/8 of the value provided in the label (based on AUC comparisons). The animal multiples of human exposure calculations were based on weekly dose comparisons for the carcinogenicity studies described in this label. The animal multiples of human exposure calculations were based on daily dose comparisons for the reproductive toxicology studies described in this label.

In an oral (gavage) rat carcinogenicity study, imiquimod was administered to Wistar rats on a 2 × /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 2 × /week in female rats (87 × MRHD based on weekly AUC comparisons), 4 mg/kg administered 2 × /week in male rats (75 × MRHD based on weekly AUC comparisons) or 3 mg/kg administered 7 × /week to male and female rats (153 × 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 3 × /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 (251 × 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 Aldara Cream, minus the active moiety (imiquimod).

In a 52-week dermal photoco-carcinogenicity study, the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing (3 × /week; 40 weeks of treatment followed by 12 weeks of observation) with concurrent exposure to UV radiation (5 days per week) with the Aldara 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 87 × MRHD based on AUC comparisons.

Pregnancy

Pregnancy Category C:

Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 1, 5 and 20 mg/kg/day imiquimod were administered during the period of organogenesis (gestational days 6 - 15) to pregnant female rats. In the presence of maternal toxicity, fetal effects noted at 20 mg/kg/day (577 × MRHD based on AUC comparisons) included increased resorptions, decreased fetal body weights, delays in skeletal ossification, bent limb bones, and two fetuses in one litter (2 of 1567 fetuses) demonstrated exencephaly, protruding tongues and low-set ears. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 5 mg/kg/day (98 × MRHD based on AUC comparisons).

Intravenous doses of 0.5, 1 and 2 mg/kg/day imiquimod were administered during the period of organogenesis (gestational days 6 - 18) to pregnant female rabbits. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 2 mg/kg/day (1.5 × MRHD based on BSA comparisons), the highest dose evaluated in this study, or 1 mg/kg/day (407 × MRHD based on AUC comparisons).

A combined fertility and peri- and post-natal development study was conducted in rats. Oral doses of 1, 1.5, 3 and 6 mg/kg/day imiquimod were administered to male rats from 70 days prior to mating through the mating period and to female rats from 14 days prior to mating through parturition and lactation. No effects on growth, fertility, reproduction or post-natal development were noted at doses up to 6 mg/kg/day (87 × MRHD based on AUC comparisons), the highest dose evaluated in this study. In the absence of maternal toxicity, bent limb bones were noted in the F1 fetuses at a dose of 6 mg/kg/day (87 × MRHD based on AUC comparisons). This fetal effect was also noted in the oral rat embryofetal development study conducted with imiquimod. No treatment related effects on teratogenicity were noted at 3 mg/kg/day (41 × MRHD based on AUC comparisons).

There are no adequate and well-controlled studies in pregnant women. Aldara Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether topically applied imiquimod is excreted in breast milk.

Pediatric Use

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

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

Geriatric Use

Of the 215 patients in the 2 × /week clinical studies evaluating the treatment of AK lesions with Aldara Cream, 127 patients (59%) were 65 years and older, while 60 patients (28%) were 75 years and older. Of the 185 patients in the 5 × /week treatment groups of clinical studies evaluating the treatment of sBCC with Aldara Cream, 65 patients (35%) were 65 years and older, while 25 patients (14%) were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. No other clinical experience has identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONS

Healthcare providers and patients may contact 3M or FDA's Medwatch to report adverse reactions by calling 1-800-328-0255 or 1-800-FDA-1088, or on the internet at http://www.fda.gov/medwatch .

Dermal safety studies involving induction and challenge phases produced no evidence that Aldara Cream causes photoallergenicity or contact sensitization in healthy skin; however, cumulative irritancy testing revealed the potential for Aldara Cream to cause irritation, and in the clinical studies application site reactions were reported in a significant percentage of study patients. Phototoxicity testing was incomplete as wavelengths in the UVB range were not included and Aldara Cream has peak absorption in the UVB range (320 nm) of the light spectrum.

Actinic Keratosis

The data described below reflect exposure to Aldara Cream or vehicle in 436 patients enrolled in two double-blind, vehicle-controlled, 2 × /week studies. Patients applied Aldara Cream or vehicle to a 25 cm ² contiguous treatment area on the face or scalp 2 × /week for 16 weeks.

Local skin reactions were collected independently of the adverse event "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 patients discontinued for local skin/application site reactions. Of the 215 patients treated, 35 patients (16%) on Aldara Cream and 3 of 220 patients (1%) on vehicle cream had at least one rest period. Of these Aldara Cream patients, 32 (91%) resumed therapy after a rest period.

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

Superficial Basal Cell Carcinoma

The data described below reflect exposure to Aldara Cream or vehicle in 364 patients enrolled in two double-blind, vehicle-controlled, 5 × /week studies. Patients applied Aldara Cream or vehicle 5 × /week for 6 weeks. The incidence of adverse events reported by > 1% of subjects during the 6 week treatment period is summarized below.

In controlled clinical studies, 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 the 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 event "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 patients received rest periods. The average number of doses not received per patient due to rest periods was 7 doses with a range of 2 to 22 doses; 79% of patients (15/19) resumed therapy after a rest period. Overall, in the clinical studies, 2% (4/185) of patients discontinued for local skin/application site reactions.

In the sBCC studies, 17 of 1266 (1.3%) imiquimod-treated patients developed treatment site infections that required a rest period off Aldara Cream and were treated with antibiotics.

External Genital Warts

In controlled clinical trials for genital warts, the most frequently reported adverse reactions were local skin and application site reactions.

These reactions were usually mild to moderate in intensity; however, severe reactions were reported with 3 × /week application. These reactions were more frequent and more intense with daily application than with 3 × /week application. Some patients also reported systemic reactions. Overall, in the 3 × /week application clinical studies, 1.2% (4/327) of the patients 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 in female and male patients treated 3X/week with Aldara Cream. 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%).

Adverse events judged to be probably or possibly related to Aldara Cream reported by more than 5% of patients are listed below; also included are soreness, influenza-like symptoms and myalgia.

Adverse events judged to be possibly or probably related to Aldara Cream and reported by more than 1% of patients included: Application Site Disorders: Wart Site Reactions (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.

POSTMARKETING ADVERSE EVENTS

The following adverse reactions have been identified during post-approval use of Aldara 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.

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. Hematological: decreases in red cell, white cell and platelet counts. Hepatic: abnormal liver function. Neuropsychiatric: agitation, cerebrovascular accident, convulsions, depression, insomnia, multiple sclerosis aggravation, paresis, suicide. Respiratory: dyspnea. Urinary System Disorders: proteinuria. Skin and Appendages: exfoliative dermatitis.

OVERDOSAGE

Persistent topical overdosing of Aldara Cream could result in an increased incidence of severe local skin reactions and may increase the risk for systemic reactions. 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.

DOSAGE AND ADMINISTRATION

The application frequency for Aldara Cream is different for each indication.

Actinic Keratosis

Aldara Cream is to be applied 2 times per week for 16 weeks to a defined treatment area on the face or scalp (but not both concurrently). The treatment area should be one contiguous area of approximately 25 cm ² (e.g., 5 cm × 5 cm). Imiquimod cream should be applied to the entire treatment area (e.g., the forehead, scalp, or one cheek).

Aldara Cream is packaged in single-use packets, with 12 packets supplied per box. Patients should be prescribed no more than 3 boxes (36 packets) for the 16 week treatment period. Unused packets should be discarded. Partially-used packets should be discarded and not reused. 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). The patient should apply no more than one packet of Aldara Cream to the contiguous treatment area at each application. Aldara Cream is 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 cream should be rubbed into the treatment area until the cream is no longer visible. Contact with the eyes, lips and nostrils should be avoided. Examples of two times per week application schedules are Monday and Thursday, or Tuesday and Friday prior to sleeping hours. Aldara Cream treatment should continue for the full 16 weeks. However, the treatment period should not be extended beyond 16 weeks due to missed doses or rest periods. Local skin reactions in the treatment area are common. Patients should contact their physician if they experience any sign or symptom in the treatment area that restricts or prohibits their daily activity or makes continued application of the cream difficult. A rest period of several days may be taken if required by the patient's discomfort or severity of the local skin reaction. The technique for proper dose administration should be demonstrated by the prescriber to maximize the benefit of Aldara Cream therapy. Handwashing before and after cream application is recommended.

Lesions that do not respond to therapy should be carefully re-evaluated and management reconsidered.

Superficial Basal Cell Carcinoma

Aldara Cream is to be applied 5 times per week for 6 weeks to a biopsy-confirmed superficial basal cell carcinoma. The target tumor should have a maximum diameter of no more than 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.

Aldara Cream is packaged in single-use packets, with 12 packets supplied per box. Patients should be prescribed no more than 3 boxes (36 packets) for the 6 week treatment period. Unused packets should be discarded. Partially-used packets should be discarded and not reused.

Aldara Cream is to be applied 5 times per week, prior to normal sleeping hours, and left on the skin for approximately 8 hours. Before applying the cream, the patient should wash the treatment area with mild soap and water and allow the area to dry thoroughly. Sufficient cream should be applied to cover the treatment area, including one centimeter of skin surrounding the tumor. The cream should be rubbed into the treatment area until the cream is no longer visible. Eye contact should be avoided. Following the treatment period, cream should be removed by washing the area with mild soap and water. An example of a 5 times per week application schedule is to apply Aldara Cream, once per day, Monday through Friday, prior to sleeping hours. Aldara Cream treatment should continue for 6 weeks. Local skin reactions in the treatment area are common. Patients should contact their physician if they experience any sign or symptom in the treatment area that restricts or prohibits their daily activity or makes continued application of the cream difficult. A rest period of several days may be taken if required by the patient's discomfort or severity of the local skin reaction. The technique for proper dose administration should be demonstrated by the prescriber to maximize the benefit of Aldara Cream therapy. Handwashing before and after cream application is recommended.

Early clinical clearance cannot be adequately assessed until resolution of local skin reactions. It is appropriate to have the first follow-up visit at approximately 12 weeks post-treatment to assess the treatment site for clinical clearance. Local skin reactions or other findings (e.g. infection) may require that a patient be seen sooner than the 12 week post-treatment visit. If there is clinical evidence of persistent tumor at the 12 week post-treatment assessment, a biopsy or other alternative intervention should be considered; the safety and efficacy of a repeat course of Aldara Cream treatment have not been established. If any suspicious lesion arises in the treatment area at any time after 12 weeks, the patient should seek a medical evaluation. See table of Estimated Clinical Clearance Rates for Superficial Basal Cell Carcinoma in the CLINICAL STUDIES section.

External Genital Warts

Aldara Cream is to be applied 3 times per week, prior to normal sleeping hours, and left on the skin for 6-10 hours. Patients should be instructed to apply Aldara Cream to external genital/perianal warts. A thin layer is applied to the wart area and rubbed in until the cream is no longer visible. The application site is not to be occluded. Following the treatment period cream should be removed by washing the treated area with mild soap and water. Examples of 3 times per week application schedules are: Monday, Wednesday, Friday; or Tuesday, Thursday, Saturday application prior to sleeping hours. Aldara Cream treatment should continue until there is total clearance of the genital/perianal warts or for a maximum of 16 weeks. Local skin reactions (erythema) at the treatment site are common. 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. The technique for proper dose administration should be demonstrated by the prescriber to maximize the benefit of Aldara Cream therapy. Handwashing before and after cream application is recommended. Aldara 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.

HOW SUPPLIED

Aldara (imiquimod) Cream, 5%, is supplied in single-use packets which contain 250 mg of the cream. Available as: box of 12 packets NDC 0089-0610-12.

Store below 25°C (77°F).

Avoid freezing.

Keep out of reach of children.

Rx only

August 2005

Patient Information

ALDARA [al dar` a] Cream, 5%

(Imiquimod)

Read the Patient Information that comes with Aldara Cream before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or treatment. If you do not understand the information, or have any questions about Aldara Cream, talk with your healthcare provider or pharmacist.

What is Aldara Cream?

Aldara Cream is a skin use only (topical) medicine used to treat:

• external genital and perianal warts in people 12 years and older
• actinic keratosis in adults with normal immune systems. Actinic keratosis is caused by too much sun exposure.
• superficial basal cell carcinoma in adults with normal immune systems when surgical methods are less appropriate. This skin cancer needs to be diagnosed by your healthcare provider.

Aldara Cream is used in different ways for the three different skin conditions it is used to treat. It is very important that you follow the instructions for your skin condition. Talk to your healthcare provider if you have questions.

Aldara Cream does not work for everyone. Aldara Cream will not cure your genital or perianal warts. New warts may develop during treatment with Aldara Cream. It is not known if Aldara Cream can stop you from spreading genital or perianal warts to other people. For your own health and the health of others, it is important to practice safer sex. Talk to your healthcare provider about safer sex practices.

Who should not use Aldara Cream?

• Aldara Cream has not been studied in children under 12 years old for external genital and perianal warts.
• Aldara Cream has not been studied in children under 18 years old for actinic keratosis or superficial basal cell carcinoma. Children usually do not get actinic keratoses or basal cell carcinoma.

Before using ALDARA Cream, tell your healthcare provider

• about all your medical conditions, including if you:
  
  • are pregnant or planning to become pregnant. It is not known if Aldara Cream can harm your unborn baby.
  • are breastfeeding. It is not known if Aldara Cream passes into your milk and if it can harm your baby.
• about all the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements. Especially tell your healthcare provider if you have had other treatments for genital or perianal warts, or actinic keratosis, or superficial basal cell carcinoma. Aldara Cream should not be used until your skin has healed from other treatments.

How should I use Aldara Cream?

• Use Aldara Cream exactly as prescribed by your healthcare provider. Aldara Cream is for skin use only. Do not take by mouth or use in or near your eyes, lips or nostrils. Do not use Aldara Cream unless your healthcare provider has taught you the right way to use it. Talk to your healthcare provider if you have any questions.
• Aldara Cream is used for several skin conditions. Use Aldara cream only on the area of your body to be treated. Your healthcare provider will tell you where to apply Aldara cream and how often and for how long to apply it for your condition. Do not use Aldara Cream longer than prescribed. Using too much Aldara Cream, or using it too often, or for too long can increase your chances for having a severe skin reaction or other side effect. Talk to your healthcare provider if Aldara Cream does not work for you.
  
  1. For external genital and perianal warts Aldara Cream is usually used once a day for 3 days a week:
     
     • Monday, Wednesday and Friday, or
     • Tuesday, Thursday and Saturday
     
     For these conditions, Aldara Cream is usually left on the skin for 6 to 10 hours. Treatment should continue until the warts are completely gone, or up to 16 weeks.
  2. For actinic keratosis Aldara Cream is usually used once a day for 2 days a week, 3 to 4 days apart, such as:
     
     • Monday and Thursday, or
     • Tuesday and Friday
     
     For this condition, Aldara Cream is usually left on the skin for about 8 hours. Treatment should continue for the full 16 weeks even if all actinic keratoses appear to be gone, unless you are told otherwise by your healthcare provider. The area you treat with Aldara Cream should be no larger than approximately the size of your forehead or one cheek (for example 2 inches by 2 inches), unless otherwise directed by your healthcare provider.
  3. For superficial basal cell carcinoma Aldara Cream is usually used once a day for 5 days a week:
     
     • Monday, Tuesday, Wednesday, Thursday and Friday

For this condition, Aldara Cream is usually left on the skin for about 8 hours. Your healthcare provider will show you how much Aldara Cream to apply to your superficial basal cell carcinoma. You should also apply Aldara Cream to a small area of skin all around the superficial basal cell carcinoma. This small area of skin should be about the size of your fingertip. Treatment should continue for the full 6 weeks, even if the superficial basal cell carcinoma appears to be gone, unless you are told otherwise by your healthcare provider.

Applying Aldara Cream

Aldara Cream should be applied just before your bedtime.

• Wash the area to be treated with mild soap and water. Allow the area to dry.
  
  • Uncircumcised males treating warts under their penis foreskin must pull their foreskin back and clean before treatment, and clean daily during the weeks of treatment.
• Wash your hands
• Open a new packet of Aldara Cream just before use
• Apply a thin layer of Aldara Cream only to the affected area or areas to be treated. Do not use more Aldara cream than is needed to cover the treatment area.
• Rub the cream in all the way to the affected area or areas.
  
  • Do not get Aldara Cream in your eyes.
  • Do not get Aldara Cream in the anus when applying to perianal warts.
  • Female patients treating genital warts must be careful when applying Aldara Cream around the vaginal opening. Female patients should take special care if applying the cream at the opening of the vagina because local skin reactions on the delicate moist surfaces can cause pain or swelling, and may cause problems passing urine. Do not put Aldara Cream in your vagina or on the skin around the genital wart.
• Do not cover the treated area with an airtight bandage. Cotton gauze dressings can be used. Cotton underwear can be worn after applying Aldara Cream to the genital or perianal area.
• Safely throw away the open packet of Aldara Cream so that children and pets cannot get it. The open packet should be thrown away even if all the Aldara Cream was not completely used.
• After applying Aldara Cream, wash your hands well.
• Leave the cream on the affected area or areas for the time prescribed by your healthcare provider. The length of time that Aldara Cream is left on the skin is not the same for the different skin conditions that Aldara Cream is used to treat. Do not bathe or get the treated area wet before the right time has passed. Do not leave Aldara Cream on your skin longer than prescribed.
• After the right amount of time has passed, wash the treated area or areas with mild soap and water.
• If you forget to apply Aldara Cream, apply the missed dose of cream as soon as you remember and then continue on your regular schedule.
• If you get Aldara Cream in your mouth or in your eyes rinse well with water right away.

What should I avoid while using Aldara Cream?

• Do not cover the treated site with bandages or other closed dressings. Cotton gauze dressings are okay to use, if needed. Cotton underwear can be worn after treating the genital or perianal area.
• Do not apply Aldara Cream in or near the eyes, lips or nostrils, or in the vagina or anus.
• Do not use sunlamps or tanning beds, and avoid sunlight as much as possible during treatment with Aldara Cream. Use sunscreen and wear protective clothing if you go outside during daylight.
• Do not have sexual contact including genital, anal, or oral sex when Aldara Cream is on your genital or perianal skin. Aldara Cream may weaken condoms and vaginal diaphragms. This means they may not work as well to prevent pregnancy. For your own health and the health of others, it is important to practice safer sex. Talk to your healthcare provider about safer sex practices.

What are the possible side effects of Aldara Cream?

The most common side effects with Aldara Cream are skin reactions at the treatment site including:

• redness
• swelling
• a sore, blister, or ulcer
• skin that becomes hard or thickened
• skin peeling
• scabbing and crusting
• itching
• burning
• changes in skin color that do not always go away

Actinic Keratosis

During treatment and until the skin has healed, your skin in the treatment area is likely to appear noticeably different from normal skin. Side effects, such as redness, scabbing, itching and burning are common at the site where Aldara Cream is applied, and sometimes the side effects go outside of the area where Aldara Cream was applied. Swelling, small open sores and drainage may also be experienced with use of Aldara Cream. You may also experience itching and/or burning. Actinic keratoses that were not seen before may appear during treatment and may later go away. If you have questions regarding treatment or skin reactions, please talk with your healthcare provider.

Superficial Basal Cell Carcinoma

During treatment and until the skin has healed, your skin in the treatment area is likely to appear noticeably different from normal skin. Side effects, such as redness, swelling and a sore are common at the site where Aldara Cream is applied. You may also experience itching or burning. Your healthcare provider will need to check the area that was treated after your treatment is finished to make sure that the skin cancer is gone. Superficial basal cell carcinoma can come back. The chances of it coming back are higher as time passes. It is very important to have regular follow-up visits with your healthcare provider to check the area to make sure your skin cancer has not come back. Ask your healthcare provider how often you should have your skin checked. Talk with your healthcare provider if you have questions about your treatment or skin reactions.

External Genital and Perianal Warts

Patients should be aware that new warts may develop during treatment, as Aldara Cream is not a cure. Many people see reddening or swelling on or around the application site during the course of treatment. If you have questions regarding treatment or local skin reactions, please talk with your healthcare provider.

You have a higher chance for severe skin reactions if you use too much Aldara Cream or use it the wrong way. Stop Aldara Cream right away and call your healthcare provider if you get any skin reactions that affect your daily activities, or that do not go away. Sometimes, Aldara Cream must be stopped for a while to allow your skin to heal. Talk to your healthcare provider if you have questions about your treatment or skin reactions.

Other side effects of Aldara Cream include headache, back pain, muscle aches, tiredness, flu-like symptoms, swollen lymph nodes, diarrhea, and fungal infections.

If the reactions seem excessive, if either skin breaks down or sores develop during the first week of treatment, if flu-like symptoms develop or if you begin to not feel well at anytime, contact your healthcare provider.

These are not all the side effects of Aldara Cream. For more information, ask your healthcare provider or pharmacist.

How do I store Aldara Cream?

• Store Aldara Cream below 77° F (25° C). Do not freeze.
• Safely throw away Aldara Cream that is out of date or that you do not need.
• Keep Aldara Cream and all medicines out of the reach of children.

General information about Aldara Cream

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Aldara Cream for a condition for which it was not prescribed. Do not give Aldara Cream to other people, even if they have the same symptoms you have.

This leaflet summarizes the most important information about Aldara Cream. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Aldara Cream that is written for the healthcare provider. If you have other questions about Aldara Cream, call 1-888-2-ALDARA. Visit our website at

http://www.Aldara.com.

What are the ingredients in Aldara Cream?

Active Ingredient: imiquimod

Inactive ingredients: isostearic acid, cetyl alcohol, stearyl alcohol, white petrolatum, polysorbate 60, sorbitan monostearate, glycerin, xanthan gum, purified water, benzyl alcohol, methylparaben, and propylparaben.

Rx Only

3m Pharmaceuticals

275-3W-01 3M Center

St. Paul, MN 55144-1000

August 2005

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