Aldara Special Precautions

General: The safety and efficacy of Imiquimod (Aldara) Cream in immunosuppressed patients have not been established. Imiquimod (Aldara) Cream administration is not recommended until the skin is completely healed from any previous drug or surgical treatment. Imiquimod (Aldara) Cream has the potential to exacerbate inflammatory conditions of the skin, including chronic graft versus host disease.
Imiquimod (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 Imiquimod (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 Imiquimod (Aldara) Cream because of concern for heightened sunburn susceptibility. Patients should be warned to use protective clothing (hat) when using Imiquimod (Aldara) Cream. Patients with sunburn should be advised not to use Imiquimod (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 Imiquimod (Aldara) Cream. Phototoxicity has not been adequately assessed for Imiquimod (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), Imiquimod (Aldara) Cream shortened the time to skin tumor formation in an animal photoco-carcinogenicity study (see Carcinogenesis, Mutagenesis, Impairment of Fertility as follows). Therefore, it is prudent for patients to minimize or avoid natural or artificial sunlight exposure.
External Genital Warts: Local skin reaction such as erythema, erosion, excoriation/flaking, and edema are common. Should severe local skin reaction occurs, the cream should be removed by washing the treatment area with mild soap and water. Treatment with Imiquimod (Aldara) Cream can be resumed after the skin reaction has subsided.
There is no clinical experience with Imiquimod (Aldara) Cream therapy immediately following the treatment of genital/perianal warts with other cutaneously applied drugs; therefore, Imiquimod (Aldara) Cream administration is not recommended until genital/perianal tissue is healed from any previous drug or surgical treatment. Imiquimod (Aldara) has a potential to exacerbate inflammatory condition of the skin.
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 Imiquimod (Aldara) Cream have not been established for patients with Basal Cell Nevus Syndrome or Xeroderma Pigmentosum.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Note: The maximum recommended human dose (MRHD) was set at 2 packets per treatment of Imiquimod (Aldara) Cream (25 mg imiquimod) for the animal multiple of human exposure ratios presented in this drug. If higher doses than 2 packets of Imiquimod (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 was noted in the clinical pharmacokinetic study conducted in actinic keratosis subjects (see Pharmacology: Pharmacokinetics under Actions). The AUC after topical application of 6 packets of Imiquimod (Aldara) Cream was 8 fold greater than AUC after topical application of 2 packets of Imiquimod (Aldara) Cream in actinic keratosis subjects. Therefore, if a dose of 6 packets per treatment of Imiquimod (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 drug. The animal multiples of human exposure calculations were based on daily dose comparisons for the reproductive toxicology studies described in this drug.
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 dermal mouse carcinogenicity study, imiquimod (up to 5 mg/kg application imiquimod or 0.3% imiquimod) 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 were 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 (Aldara) Cream, minus the active moiety (imiquimod). In a 52-week dermal photococarcinogenicity 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 (Aldara) Cream vehicle alone.
No additional effect on tumor development beyond the vehicle effect was noted with the addition of the ingredient, imiquimod, to the vehicle cream. Imiquimod revealed no evidence of mutagenic or clastogenic potential based on the results of 5 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 3 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.
Use in Pregnancy: Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women.
Imiquimod was not found to be teratogenic in rat or rabbit teratology studies. In rats at a high maternally toxic dose (28 times human dose on a mg/m² basis), reduced pup weights and delayed ossification were observed. In developmental studies with offspring of pregnant rats treated with imiquimod (8 times human dose), no adverse effects were demonstrated.
Use in Lactation: It is not known whether topically applied imiquimod is excreted in breast milk.
Use in Children: Safety and efficacy in patients with external genital/perianal warts below the age of 12 years have not been established. sBCC is not generally seen within the pediatric population. The safety and efficacy of Imiquimod (Aldara) Cream for sBCC in patients less than 18 years have not been established.
Use in the Elderly: Of the 185 patients in the 5X/week treatment groups of clinical studies evaluating the treatment of sBCC with Aldara, 65 patients (35%) were 65 years and older, wile 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.