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Indications/Uses
For the treatment of external genital and perianal warts (condylomata acuminata) and small superficial basal cell carcinomas (sBCCs) in adult patients.
Usage: Imiquimod (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 Imiquimod (Aldara) Cream have not been established for other types of basal cell carcinomas, including nodular, morpheaform (fibrosing or sclerosing) types.
Usage: Imiquimod (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 Imiquimod (Aldara) Cream have not been established for other types of basal cell carcinomas, including nodular, morpheaform (fibrosing or sclerosing) types.
Dosage/Direction for Use
(The application frequency for Imiquimod (Aldara) Cream is different for each indication.)
External Genital Warts: Imiquimod (Aldara) Cream is to be applied 3 times/week, prior to normal sleeping hours, and left on the skin for 6 to 10 hours. Patients should be instructed to apply Imiquimod (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, the cream should be removed by washing the treated area with mild soap and water. Examples of 3 times/week application schedules are: Monday, Wednesday, Friday; or Tuesday, Thursday, Saturday application prior to sleeping hours.
Imiquimod (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 Imiquimod (Aldara) Cream therapy. Handwashing before and after cream application is recommended.
Imiquimod (Aldara) 5% Cream is packaged in single-use packets which contain sufficient cream to cover a wart area of up to 20 cm2; use of excessive amounts of cream should be avoided.
Superficial Basal Cell Carcinoma: Imiquimod (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. (See Table 5.)
External Genital Warts: Imiquimod (Aldara) Cream is to be applied 3 times/week, prior to normal sleeping hours, and left on the skin for 6 to 10 hours. Patients should be instructed to apply Imiquimod (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, the cream should be removed by washing the treated area with mild soap and water. Examples of 3 times/week application schedules are: Monday, Wednesday, Friday; or Tuesday, Thursday, Saturday application prior to sleeping hours.
Imiquimod (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 Imiquimod (Aldara) Cream therapy. Handwashing before and after cream application is recommended.
Imiquimod (Aldara) 5% Cream is packaged in single-use packets which contain sufficient cream to cover a wart area of up to 20 cm2; use of excessive amounts of cream should be avoided.
Superficial Basal Cell Carcinoma: Imiquimod (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. (See Table 5.)
Patients should be prescribed no more than 3 boxes (36 sachets) for the 6 week treatment period.
Unused packets should be discarded. Partially-used packets should be discarded and not reused. Imiquimod (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 1 cm 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 Imiquimod (Aldara) Cream, once per day, Monday through Friday, prior to sleeping hours. Imiquimod (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 is 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 Imiquimod (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 weeks 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 Imiquimod (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 4 in Pharmacology: Pharmacokinetics: Clinical studies under Actions.
Unused packets should be discarded. Partially-used packets should be discarded and not reused. Imiquimod (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 1 cm 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 Imiquimod (Aldara) Cream, once per day, Monday through Friday, prior to sleeping hours. Imiquimod (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 is 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 Imiquimod (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 weeks 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 Imiquimod (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 4 in Pharmacology: Pharmacokinetics: Clinical studies under Actions.
Overdosage
Persistent topical overdosing of Imiquimod (Aldara) Cream could result in an increased incidence of severe local skin reaction 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 IV fluid administration.
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.
It should be discontinued if hypersensitivity to any of its ingredients is noted.
Warnings
Imiquimod (Aldara) Cream has not been evaluated for the treatment of urethral, intravaginal, cervical, rectal or intra-anal human papilloma viral disease and is not recommended for these conditions. The diagnosis of sBCC should be confirmed prior to treatment since safety and effectiveness of Imiquimod (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 (ie, sBCC). Patients with sBCC treated with Imiquimod (Aldara) Cream are recommended to have regular follow-up of treatment site. See Table 4 in Pharmacology: Pharmacokinetics: Clinical studies under Actions.
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.
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.
Use In Pregnancy & Lactation
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.
Nursing Mothers: It is not known whether topically applied imiquimod is excreted in breast milk.
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.
Nursing Mothers: It is not known whether topically applied imiquimod is excreted in breast milk.
Adverse Reactions
Dermal safety studies involving induction and challenge phases produced no evidence that Imiquimod (Aldara) Cream causes photoallergenicity or contact sensitization in healthy skin; however, cumulative irritancy testing revealed the potential for Imiquimod (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 has peak absorption in the UVB range (320 nm) of the light spectrum.
External Genital Warts: In controlled clinical trials, the most frequently reported adverse reaction were those of local skin and application site reactions; some patients also reported systemic reactions. These reactions were usually mild to moderate in intensity; however, severe reactions were reported with 3X/week application. These reactions were more frequent and more intense with daily application than with 3 times per week application. Overall, in the 3X/week application clinical studies, 1.2% (4/327) of the patients discontinued due to local skin/application site reaction.
The incidence and severity of local skin reactions during controlled clinical trials are shown in the following table. (See Table 6.)
External Genital Warts: In controlled clinical trials, the most frequently reported adverse reaction were those of local skin and application site reactions; some patients also reported systemic reactions. These reactions were usually mild to moderate in intensity; however, severe reactions were reported with 3X/week application. These reactions were more frequent and more intense with daily application than with 3 times per week application. Overall, in the 3X/week application clinical studies, 1.2% (4/327) of the patients discontinued due to local skin/application site reaction.
The incidence and severity of local skin reactions during controlled clinical trials are shown in the following table. (See Table 6.)
Remote site skin reactions were also reported in female and male patients treated 3 times per week with Imiquimod (Aldara) 5% 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 Imiquimod (Aldara) Cream reported by >5% of patients are listed in Table 7; also included are soreness, influenza-like symptoms and myalgia. (See Table 7.)
Adverse events judged to be probably or possibly related to Imiquimod (Aldara) Cream reported by >5% of patients are listed in Table 7; also included are soreness, influenza-like symptoms and myalgia. (See Table 7.)
Adverse events judged to be possibility or probability related to Aldara and reported by >1% of patients includes: 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.
Gastrointestinal System Disorders: Diarrhea.
Musculoskeletal System Disorders: Myalgia.
Superficial Basal Cell Carcinoma: The data described in the following text reflect exposure to Aldara or vehicle in 364 patients enrolled in 2 double-blind, vehicle-controlled, 5 times per week studies. Patients applied Imiquimod (Aldara) Cream or vehicle 5X/week for 6 weeks. The incidence of adverse events reported by >1% of subjects during the 6 week treatment period is summarized in the following table. (See Table 8.)
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.
Gastrointestinal System Disorders: Diarrhea.
Musculoskeletal System Disorders: Myalgia.
Superficial Basal Cell Carcinoma: The data described in the following text reflect exposure to Aldara or vehicle in 364 patients enrolled in 2 double-blind, vehicle-controlled, 5 times per week studies. Patients applied Imiquimod (Aldara) Cream or vehicle 5X/week for 6 weeks. The incidence of adverse events reported by >1% of subjects during the 6 week treatment period is summarized in the following table. (See Table 8.)
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 weeks treatment period is summarized in the following table. (See Table 9.)
The incidence of the application site reactions reported by >1% of the subjects during the 6 weeks treatment period is summarized in the following table. (See Table 9.)
Local skin reactions were collected independently of the adverse event "application site reaction" in an effort to provide a better picture of 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. (See Table 10.)
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 patients 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 Imiquimod (Aldara) Cream and were treated with antibiotics.
Storage
Do not store above 25°C. Avoid freezing.
Action
Pharmacology: Pharmacodynamics: External Genital Warts: Imiquimod has no direct antiviral activity in cell culture. A study in 22 patients with genital/perianal warts comparing Imiquimod (Aldara) Cream and vehicle shows that Imiquimod (Aldara) Cream induces mRNA encoding cytokines including interferon-α 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.
Superficial Basal Cell Carcinoma: The mechanism of action of Imiquimod (Aldara) Cream in treating superficial basal cell carcinoma (sBCC) lesions is unknown. An open label study in 6 subjects with sBCC suggests that treatment with Imiquimod (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.
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 study. Mean urinary recoveries of imiquimod and metabolites combined over the whole course of treatment, expressed aspercent 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 actinic keratosis 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 the face (12.5 mg imiquimod, 1 single-use sachet), scalp (25 mg, 2 sachets) and hands/arms (75 mg, 6 sachets), respectively. (See Table 1).
In addition HPVL1 mRNA and HPV DNA are significantly decreased following treatment. However, the clinical relevance of these findings is unknown.
Superficial Basal Cell Carcinoma: The mechanism of action of Imiquimod (Aldara) Cream in treating superficial basal cell carcinoma (sBCC) lesions is unknown. An open label study in 6 subjects with sBCC suggests that treatment with Imiquimod (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.
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 study. Mean urinary recoveries of imiquimod and metabolites combined over the whole course of treatment, expressed aspercent 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 actinic keratosis 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 the face (12.5 mg imiquimod, 1 single-use sachet), scalp (25 mg, 2 sachets) and hands/arms (75 mg, 6 sachets), respectively. (See Table 1).
The application surface area was not controlled when more than one sachet 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 sachets) for males and females, respectively following 3 applications per week for 16 weeks.
Clinical Studies: External Genital Warts: In a double-blind, placebo-controlled clinical study, 209 otherwise healthy patients ≥18 years with genital/perianal warts were treated with Imiquimod (Aldara) Cream or vehicle control 3X/week for a maximum of 16 weeks. The median baseline warts area was 69 mm2 (range 8-5525 mm2). Patient accountability is shown in Figure 1. (See Figure 1.)
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 sachets) for males and females, respectively following 3 applications per week for 16 weeks.
Clinical Studies: External Genital Warts: In a double-blind, placebo-controlled clinical study, 209 otherwise healthy patients ≥18 years with genital/perianal warts were treated with Imiquimod (Aldara) Cream or vehicle control 3X/week for a maximum of 16 weeks. The median baseline warts area was 69 mm2 (range 8-5525 mm2). Patient accountability is shown in Figure 1. (See Figure 1.)
Data on complete clearance are listed in Table 2. The median time to complete wart clearance was 10 weeks. (See Table 2.)
Superficial Basal Cell Carcinoma: In two double-blind, vehicle-controlled clinical studies, 364 patients with primary superficial basal cell carcinoma (sBCC) were treated with Imiquimod (Aldara) Cream or vehicle cream 5X/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 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, 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; 5X/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.
Patients outcome are shown in the figure as follows. (See Figure 2.)
Patients outcome are shown in the figure as follows. (See Figure 2.)
Of Imiquimod (Aldara)-treated patients 6% (11/178) who 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 as follows. (See Table 3.)
An open-label 5-year study (study E) is ongoing to assess the recurrence of sBCC treated with Imiquimod (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 in the previous text. At 12-week 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 years (24 months) follow-up data are available from this study and are presented in the following table: (See Table 4.)
MedsGo Class
Warts & Calluses Preparations
Features
Brand
Aldara
Full Details
Dosage Strength
50 mg / g
Drug Ingredients
- Imiquimod
Drug Packaging
Cream 1's
Generic Name
Imiquimod
Dosage Form
Cream
Registration Number
DR-XY23952
Drug Classification
Prescription Drug (RX)