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imiquimod 5% cream packet generic aldara

In stock Manufacturer PERRIGO CO. 45802036862
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Uses

Imiquimod is used topically for the treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratosis on the face or scalp in immunocompetent adults; treatment of biopsy-confirmed, primary superficial basal cell carcinoma in immunocompetent adults; and treatment of external genital and perianal exophytic warts (condylomata acuminata) caused by human papillomavirus (HPV). Imiquimod has not been evaluated in controlled clinical studies for the topical treatment of verruca vulgaris (common warts). Although imiquimod has been used topically for the treatment of molluscum contagiosum, safety and efficacy have not been established.

Actinic Keratosis

Imiquimod is used for the topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratosis on the face or scalp in immunocompetent adults.

Safety and efficacy of topical imiquimod for the treatment of actinic keratosis have been evaluated in 2 double-blind, vehicle-controlled studies that included 436 adults with actinic keratosis (4-8 clinically typical, visible, discrete, nonhyperkeratotic, nonhypertrophic lesions within a contiguous area no larger than 25 cm occurring on either the face or scalp). Patients were randomized to receive topical imiquimod 5% cream or vehicle placebo twice weekly for 16 weeks, and clinical response was evaluated 8 weeks after the last dose. Complete clearance was defined as no visible actinic keratosis lesions in the treatment area, with clearance of baseline lesions as well as any new or subclinical lesions that appeared during treatment. Complete clearance occurred in 44-46% of patients treated with imiquimod compared with 3-4% of patients treated with placebo. There was partial clearance of actinic keratosis lesions (clearance of at least 75% of baseline lesions) in 58-60% of those treated with imiquimod compared with 10-14% of those treated with placebo. During treatment, 48% of patients had an increase in the number of actinic keratosis lesions in the treatment area relative to baseline; this did not affect the response to treatment.

In one randomized, double-blind, vehicle-controlled study in adults with a histologic diagnosis of multiple actinic keratoses, topical imiquimod (3 times weekly for up to 12 weeks) resulted in clinical clearance of lesions in 84% and partial clearance of lesions in 8% of patients; clearance of lesions was histologically confirmed 2 weeks after the last application of imiquimod. There was no reduction in size or number of actinic keratosis lesions in patients who received placebo.

Basal Cell Carcinoma

Imiquimod is used for the topical treatment of biopsy-confirmed, primary superficial basal cell carcinoma in immunocompetent adults. Safety and efficacy of the drug have not been established for the treatment of any other type of basal cell carcinoma, including nodular and morpheaform (fibrosing or sclerosing) types.

Topical imiquimod should be used for the treatment of superficial basal cell carcinoma only when the diagnosis has been confirmed histologically, the tumor diameter is 2 cm or less, the tumor is located on the trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet), and surgical methods are medically less appropriate and patient follow-up can be reasonably assured. Safety and efficacy of imiquimod for the treatment of superficial basal cell carcinoma that occurs on the face, head, or anogenital area have not been established.

In 2 double-blind, vehicle-controlled studies in 364 adults with primary superficial basal cell carcinoma (biopsy-confirmed tumors with a minimum area of 0.5 cm and a maximum diameter of 2 cm), patients were randomized to receive topical imiquimod 5% cream or vehicle placebo 5 times weekly for 6 weeks. Efficacy was assessed 12 weeks after the last dose and a complete response was defined as the proportion of patients with clinical (visual) and histologic clearance of the superficial basal cell carcinoma lesion. At 12 weeks after treatment, 75% of those treated with imiquimod had clinical and histologic clearance compared with 2% of those treated with placebo. Long-term follow-up of those with no clinical evidence of superficial basal cell carcinoma 12 weeks after treatment indicate that 84% still had clinical clearance 1 year later and 79% still had clinical clearance 2 years later.

Human Papillomavirus Infections

External Genital and Perianal HPV Warts

Imiquimod is used for the topical treatment of external genital and perianal HPV warts. Safety and efficacy of topical imiquimod for the treatment of urethral, intravaginal, cervical, rectal, or anal HPV warts have not been established. Some clinicians suggest that use of the drug may be considered for the treatment of distal meatal HPV warts; however, data are limited. Imiquimod should not be used to treat subclinical genital HPV infection (without exophytic warts).

Regimens recommended by the US Centers for Disease Control and Prevention (CDC) and others for the treatment of external genital and perianal exophytic HPV warts are topical therapies for self-administration (imiquimod 5%, podofilox 0.5%); topical therapies that must be administered by a health-care provider (podophyllum resin 10-25%, trichloroacetic acid [TCA] 80-90%, bichloroacetic acid [BCA] 80-90%); or surgical techniques (cryotherapy, electrosurgery, surgical excision). Alternative regimens include intralesional interferon alfa or laser surgery. The CDC and others recommend that selection of therapy for the treatment of exophytic warts be guided by the preference of the patient, available resources, experience of the health-care provider, factors related to the warts (e.g., size, number, morphology, anatomic site involved), and factors related to the therapy (e.g., cost, convenience, adverse effects). There is some evidence that warts located on moist surfaces and/or in intertriginous areas appear to respond better to topical treatments (e.g., imiquimod, podofilox, podophyllum resin, TCA) than warts on drier surfaces; however, there is no clear evidence that any one therapy is superior to any other therapy and no single treatment is ideal for all patients or all warts. Overly aggressive treatment should be avoided and the risks versus benefits of the therapy selected should be evaluated throughout treatment; therapy should be changed if the desired response is not obtained.

The primary goal of treating exophytic genital and perianal HPV warts is the destruction or clearance of visible, symptomatic warts. Most patients have fewer than 10 genital warts with a total wart area of 0.5-1 cm, and treatment with recommended regimens generally can induce wart-free periods. Without treatment, exophytic genital and perianal HPV warts may spontaneously regress, remain unchanged, or increase in size or number becoming painful and a source of psychological trauma. No currently available therapy for exophytic genital and perianal warts, including imiquimod, has been shown to eradicate HPV (i.e., produce a virologic cure) or affect the natural history of HPV infection. In addition, while there is some evidence that exophytic warts play a role in transmission of HPV to sexual partners, it is unclear whether treating these warts has any effect on transmission of the virus. Existing data indicate that currently treatment regimens may reduce, but probably do not eradicate, infectivity. It is unclear whether reduction in viral DNA following treatment impacts future transmission of the virus. HPV apparently may establish one or more sites of latent infection following primary infection with the virus. Despite the use of therapies that effectively result in the destruction or clearance of exophytic HPV warts, latent or subclinical HPV infection can persist and recurrence of visible warts commonly occurs.

Exophytic genital and perianal warts generally are caused by HPV types 6 or 11. Other HPV types (e.g., types 16, 18, 31, 33, 35) sometimes are present in the anogenital region, may be present in visible warts, and have been strongly associated with vaginal, anal, and cervical intraepithelial dysplasia and squamous cell carcinoma. Individuals with visible genital warts often are infected simultaneously with multiple HPV types. Because HPV genital and perianal warts have a characteristic appearance, biopsy to confirm the diagnosis generally is necessary only if the diagnosis is uncertain, warts do not respond to standard therapies, the disease worsens during therapy, the patient is immunocompromised, and/or warts are pigmented, indurated, fixed, and ulcerated. Tests for detecting HPV DNA are widely available, but the clinical usefulness of these tests in the routine diagnosis or management of visible genital or perianal warts has not been determined.

Follow-up visits are not required for patients self-administering treatment but may be useful several weeks after initiation of therapy to determine the response to treatment and to monitor for and treat complications of therapy. If visible genital and perianal warts have cleared after treatment, follow-up examination is not mandatory; however, a follow-up evaluation 3 months after treatment may be beneficial since external genital warts can be difficult to identify. Earlier follow-up visits may benefit certain patients by providing the clinician the opportunity to document the absence of warts, monitor for and treat complications of therapy, and provide additional patient education and counseling. Patients should be cautioned to watch for recurrences and advised that such recurrences occur most frequently during the first 3 months. Examination of sexual partners is not necessary for the management of genital HPV warts because no data indicate that reinfection plays a role in recurrences and, in the absence of curative therapy, treatment to reduce transmission is not realistic. However, sexual partners of patients with genital HPV warts may benefit from examination to assess the presence of HPV warts or other sexually transmitted diseases and also may benefit from counseling about the implications of having a partner who has HPV warts. Women with genital HPV warts should be advised to undergo regular Papanicolaou (Pap) tests as recommended for women without genital warts.

Clinical Experience

Safety and efficacy of topical imiquimod for the treatment of external genital and perianal warts have been evaluated in several double-blind, placebo-controlled studies in otherwise healthy adults 18 years of age or older. In a phase III study in adults who had biopsy-confirmed external genital and/or perianal HPV warts, patients were randomized to receive imiquimod 5% cream, imiquimod 1% cream (not commercially available), or vehicle placebo 3 times weekly for up to 16 weeks. At the end of 16 weeks, results of the intent-to-treat analysis indicated that there was complete clearance of visible warts in 50% of those who received imiquimod 5% cream, 21% of those who received imiquimod 1% cream, and 11% of those who received vehicle placebo. Results of the treatment failures analysis indicated that complete clearance of visible warts occurred in 56% of those who received imiquimod 5% cream, 27% of those who received imiquimod 1% cream, and 14% of those who received vehicle placebo; there was a 50% or greater reduction in total wart area in 81, 41, or 31% of patients, respectively. Warts generally cleared within 8-12 weeks. The clearance rate was higher and the median time to complete wart clearance was shorter in females than in males; this difference may be due to differences in keratinization of wart tissue. Based on the treatment failures analysis, there was complete clearance of visible warts in 77% of females and 40% of males receiving imiquimod 5% cream. Of those patients who had complete clearance of warts during imiquimod therapy and who were available for a 12-week follow-up, 13% had a recurrence of at least one wart; there was no gender-related difference in recurrence rates.

HIV-infected Individuals

Imiquimod 5% cream has been used for the topical treatment of external genital and perianal HPV warts in a limited number of adults with human immunodeficiency virus (HIV) infection; however, the response rate appears to be lower in these individuals than in those who are not HIV infected. (See Cautions: Precautions and Contraindications.) In a phase I, double-blind, vehicle-controlled study in HIV-infected patients 18 years of age or older, results of the intent-to-treat analysis indicated that 11% of those who received imiquimod and 6% of those who received placebo had complete clearance of warts. In addition, adverse effects reported in this patient population (e.g., mild to moderate local reactions including erythema) were similar to those reported when the drug is used in otherwise healthy adults with HPV warts.

For the treatment of external HPV warts in HIV-infected adults and adolescents, the CDC, National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) generally recommend a patient-applied topical therapy (imiquimod 5%, podofilox 0.5%) for uncomplicated lesions and a topical therapy administered by a health-care provider (podophyllum resin 10-25%, TCA, BCA) or a surgical technique (cryotherapy, electrosurgery, surgical excision) for complex or multicentric lesions or those that are inaccessible to patient-applied treatments. Although topical agents (podofilox 0.5%, imiquimod 5%, podophyllum resin, TCA 80-90%) are recommended as alternatives for the treatment of HPV warts in HIV-infected children, the CDC, NIH, and IDSA state that topical therapy often is ineffective in these patients and use of a surgical technique (cryotherapy, electrosurgery) may be preferred.

Molluscum Contagiosum

Topical imiquimod has been effective when used in a limited number of adults and children for the treatment of molluscum contagiosum. However, safety and efficacy for treatment of molluscum contagiosum have not been established. Results of 2 randomized, double-blind, vehicle-controlled studies in 702 children 2-12 years of age with molluscum contagiosum indicate that topical imiquimod (3 times weekly for up to 16 weeks) is no more effective than placebo in these patients.

Molluscum contagiosum generally is a benign, cutaneous viral infection characterized by discrete, smooth-surfaced, pearly pink or white, papular skin lesions that may have a central umbilication. While these lesions may resolve spontaneously in immunocompetent individuals, they can become widespread as a result of scratching (especially in children) and the infection tends to be more severe in individuals who have eczema or are immunosuppressed, including those with HIV infection. Molluscum contagiosum can be transmitted through direct contact (e.g., skin-to-skin contact, sexual contact) and by fomites such as towels.

Dosage and Administration

Administration

Imiquimod is applied topically as a 5% cream.

The topical cream is for external use only. Contact with the eyes, lips, and nostrils should be avoided and the drug should not be administered orally, intravaginally, or intra-anally.

Imiquimod is suitable for self-administration. Prior to initial use, patients should be instructed regarding proper techniques for application and removal of the drug.

Patients should be directed to wash their hands before and after applying imiquimod cream. Prior to application, the affected area should be washed with mild soap and water and allowed to dry thoroughly (at least 10 minutes). Immediately prior to normal sleeping hours (bedtime) on treatment days, the cream should be applied to the entire treatment area and rubbed in until no longer visible. The cream should be allowed to remain on the skin for approximately 8 hours (6-10 hours) and removed the following morning by washing with mild soap and water.

When the drug is used for the treatment of genital HPV warts, uncircumcised males should be advised to clean under the foreskin before treatment and once daily during treatment and females should be advised to avoid intravaginal application and take special care when applying near the vaginal opening since local reactions at this site may result in pain or swelling and difficult urination.

Use of imiquimod should be delayed until skin has healed from any previous sunburn or drug or surgical treatment.

Occlusive dressings or wrappings should not be used.

Imiquimod cream is supplied in single-use packets containing 250 mg of cream (12.5 mg of imiquimod). When treating actinic keratosis, no more than 1 packet of the cream should be applied to the contiguous treatment area. When treating external genital or perianal human papillomavirus (HPV) warts, 1 packet of cream should be sufficient to cover a wart area up to 20 cm. Partially used packets should be discarded and should not be reused.

Dosage

Because of the potential for adverse local reactions (e.g., erythema, erosion, excoriation/flaking, edema), the recommended dose, frequency of application, and duration of treatment of topical imiquimod should not be exceeded; use of excessive amounts of the cream should be avoided. Topical imiquimod therapy may be temporarily discontinued for several days if required because of the patient's discomfort or severity of local reactions, and then reinitiated after the reactions subside. However, the total duration of treatment should not be extended beyond the maximum recommended duration (i.e., 16 weeks for treatment of actinic keratosis, 6 weeks for treatment of superficial basal cell carcinoma, 16 weeks for treatment of genital and perianal HPV warts).

Actinic Keratosis

For the topical treatment of actinic keratosis in adults, a thin layer of imiquimod 5% cream should be applied to the affected area of the face or scalp at bedtime twice weekly (e.g., Monday and Thursday or Tuesday and Friday) for 16 weeks. The drug should be removed the following morning (6-10 hours after application) by washing with soap and water.

The treatment area should be a single contiguous area approximately 25 cm (e.g., 5 cm long and 5 cm wide) occurring on the face (e.g., forehead or one cheek) or on the scalp. Both areas should not be treated concurrently. The safety and efficacy of treating actinic keratosis in an area larger than 25 cm have not been established.

The response to treatment should be assessed after local skin reactions and/or application site reactions have resolved. Lesions that do not respond to treatment should be carefully reevaluated and management reconsidered. The safety and efficacy of repeat courses of imiquimod in the same treatment area have not been established.

Basal Cell Carcinoma

For the topical treatment of biopsy-confirmed, primary superficial basal cell carcinoma in adults, a thin layer of imiquimod 5% cream should be applied to the affected area at bedtime 5 times weekly (e.g., Monday through Friday) for 6 weeks. The drug should be removed the following morning (6-10 hours after application) by washing with soap and water.

The treatment area should include the target tumor and a 1-cm margin of skin around the tumor.(See Table.)

Table 1. Dosage for Treatment of Superficial Basal Cell Carcinoma
Target Tumor Diameter (cm) Cream Droplet Diameter (mm) Approximate Dosage in Cream Droplet
0.5 to less than 1 4 10 mg 5 times weekly for 6 weeks
1 to less than 1.5 5 25 mg 5 times weekly for 6 weeks
1.5 to 2 cm 7 40 mg 5 times weekly for 6 weeks

The response to treatment should be assessed after local skin reactions and/or application site reactions have resolved and skin has regenerated (approximately 12 weeks after treatment ends). If there is clinical evidence of persistent tumor after treatment, a biopsy or other alternative intervention should be considered. Lesions that do not respond to treatment should be carefully reevaluated and management reconsidered. The safety and efficacy of repeat courses of imiquimod in the same treatment area have not been established.

Human Papillomavirus (HPV) Infections

External Genital and Perianal HPV Warts

For the topical treatment of external genital and perianal HPV warts in adults and adolescents 12 years of age and older, a thin layer of imiquimod 5% cream should be applied to the affected area at bedtime 3 times weekly (e.g., Monday, Wednesday, Friday or Tuesday, Thursday, Saturday). The drug should be removed the following morning (6-10 hours after application) by washing with soap and water.

Topical imiquimod therapy should be continued until total clearance of HPV warts has occurred or for a maximum of 16 weeks. In many patients, clearance of external HPV warts occurs within 8-12 weeks.

If used for the treatment of genital or perianal HPV warts in HIV-infected adults, adolescents, or children, a thin layer of 5% cream should be applied to the wart area at bedtime 3 times weekly (nonconsecutive days) for up to 16 weeks. The drug should be removed the following morning by washing with soap and water.

Although follow-up examinations are not generally required for patients self-administering imiquimod for the treatment of HPV warts, an examination several weeks after initiation of therapy may be useful to determine the response to treatment, to monitor and treat complications of therapy, and to provide additional patient education and counseling. A follow-up examination 3 months after completion of treatment may be beneficial since identification of external genital warts may be difficult.

Cautions

Imiquimod generally is well tolerated when applied topically. The most frequent adverse effects of the drug are mild to moderate local inflammatory reactions; these effects have been severe enough to require discontinuance of the drug in 1-4% of patients. Serious adverse systemic effects have not been reported to date with topical imiquimod.

Local and Dermatologic Effects

Adverse local reactions, including erythema, erosion, excoriation/flaking, and edema, commonly occur at the site of application of imiquimod and/or surrounding areas. These reactions usually are mild to moderate in severity; however, severe local reactions have been reported.

In controlled studies in adults with actinic keratosis, the most frequently reported local skin reactions in those receiving imiquimod 5% cream (twice weekly for 16 weeks) were erythema (97%), flaking/scaling/dryness (93%), scabbing/crusting (79%), edema (49%), erosion/ulceration (48%), weeping/exudate (22%), and vesicles (9%). Application site reactions (e.g., bleeding, burning, induration, irritation, pain, pruritus, stinging, tenderness) occurred in 33% of those receiving topical imiquimod compared with 14% of those receiving placebo. In these studies, 16% of patients discontinued imiquimod treatment because of local or application site reactions and 91% of these were able to resume treatment after a rest period.

In controlled studies in adults with superficial basal cell carcinoma, the most frequently reported local skin reactions in those receiving imiquimod 5% cream (5 times weekly for 6 weeks) were erythema (100%), flaking/scaling (91%), induration (84%), scabbing/crusting (83%), edema (78%), erosion (66%), ulceration (40%), and vesicles (31%). Application site reactions were reported in 28% of those receiving topical imiquimod compared with 3% of those receiving placebo and included bleeding, burning, erythema, edema, induration, erosion, flaking/scaling, scabbing/crusting, pain, papule, and pruritus. In these studies, 10% of patients discontinued imiquimod treatment because of local or application site reactions and 79% of these were able to resume treatment after a rest period. In addition, 1.3% of patients developed treatment site infections that required temporary discontinuance of the drug and treatment with anti-infectives.

When imiquimod 5% cream was used in controlled studies in patients with genital and perianal HPV warts (3 times weekly for up to 16 weeks), erythema occurred in 58-65%, erosion in 30-31%, excoriation/flaking in 18-26%, edema in 12-18%, scabbing in 4-13%, induration in 5-7%, ulceration in 4-8%, and vesicles in 2-3% of those receiving the drug. In addition, application site reactions in those receiving the drug included pruritus (22-32%), burning (9-26%), pain (2-8%), and soreness (0-3%). In addition, fungal infections occurred in 2-11% of patients receiving the drug. Overall, 1.2% of patients in these studies discontinued treatment because of local or application site reactions.

Adverse dermatologic reactions at sites away from the site of application have been reported in some patients receiving topical imiquimod. Remote site reactions have included bleeding, burning, edema, erosion, erythema, excoriation/flaking, induration, pain, pruritus, tenderness, tinea cruris, and ulceration.

Topical imiquimod therapy may result in an increased susceptibility to sunburn following exposure to natural or artificial sunlight.(See Cautions: Precautions and Contraindications.) Although provocative, repeat insult patch test studies involving induction and challenge phases produced no evidence that topical imiquimod cream causes photoallergenicity or contact sensitization in healthy skin, cumulative irritancy testing revealed the potential of the cream to cause irritation.

Localized hypopigmentation or hyperpigmentation also has been reported. Available follow-up data suggest that skin color changes (i.e., hypopigmentation, hyperpigmentation) may be permanent in some patients.

Systemic Effects

Adverse systemic effects have been reported rarely in patients receiving topical imiquimod. Flu-like signs and symptoms may accompany or precede local inflammatory reactions and may include fever, malaise, myalgias, nausea, and rigors. These symptoms may be severe enough to require temporary discontinuance of the drug.

In controlled studies in adults with actinic keratosis, adverse systemic effects reported in more than 1% of those receiving imiquimod 5% cream (twice weekly for 16 weeks) were upper respiratory tract infection (15%), sinusitis (7%), headache (5%), squamous carcinoma (4%), diarrhea (3%), and eczema (2%).

In controlled studies in adults with superficial basal cell carcinoma, adverse systemic effects reported in more than 1% of those receiving imiquimod 5% cream (5 times weekly for 6 weeks) were headache (8%), back pain (4%), upper respiratory tract infection (3%), rhinitis (3%), lymphadenopathy (3%), fatigue (2%), sinusitis (2%) dyspepsia (2%), coughing (2%), and fever (2%).

In controlled studies in patients with external genital and perianal HPV warts, adverse systemic effects reported in more than 1% of those who received imiquimod cream were headache (4%) and influenza-like symptoms (3%).

Precautions and Contraindications

Although adverse reactions to topical imiquimod usually consist of mild to moderate local skin reactions, severe local inflammatory reactions (e.g., skin weeping, erosion) that may be accompanied or preceded by flu-like signs or symptoms can occur. In addition, topical imiquimod has the potential to exacerbate inflammatory skin conditions. To minimize the potential for local reactions during topical imiquimod therapy, the manufacturer recommends that the drug be washed off the treatment area with mild soap and water approximately 8 hours (6-10 hours) after each dose.(See Dosage and Administration: Administration.) If a severe local reaction occurs, imiquimod should be washed off the treatment area with mild soap and water. If necessary, the drug may be discontinued for several days and then reinitiated after these reactions subside. Nonocclusive dressing (e.g., cotton gauze, cotton underwear) may be used in the management of skin reactions.

Because of a possible increased risk of sunburn, exposure to sunlight (including sunlamps) should be avoided or minimized during topical imiquimod therapy. Patients should be warned to use protective clothing (e.g., hat) during imiquimod treatment. The drug should be used with caution in those who may have considerable sun exposure (e.g., occupational) and in those sensitive to sunlight.

Imiquimod therapy should not be initiated until skin has healed from any previous sunburn or drug or surgical treatment.

Safety and efficacy of imiquimod in immunosuppressed patients have not been established. Immunosuppressed individuals, including those with human immunodeficiency virus (HIV) infection, may have less of a response to treatment of genital and perianal HPV warts than immunocompetent individuals and may have more frequent recurrences after treatment. In addition, biopsy to confirm a diagnosis of HPV warts may be required more frequently in immunosuppressed individuals since squamous cell carcinomas arising in or resembling HPV warts might occur more frequently in these individuals.

Patients receiving topical imiquimod for the treatment genital or perianal HPV warts should be advised that imiquimod is not a cure for HPV infection, that new HPV warts may develop during or after treatment, and that the effect of the drug on transmission of HPV is unknown. Patients should be instructed not to rely on condoms or diaphragms to prevent sexually transmitted diseases or pregnancy during topical imiquimod therapy since the cream may damage these devices and result in protective failure. Patients should be warned to avoid sexual contact (e.g., genital, anal, oral) while imiquimod is on the skin. Patients also should be informed that changes in skin pigmentation (hypopigmentation or hyperpigmentation) may occur at the application site and occasionally may be permanent.

Pediatric Precautions

Safety and efficacy of imiquimod topical cream for the treatment of actinic keratosis or superficial basal cell carcinoma in children younger than 18 years of age have not been established. These skin conditions generally do not occur in children.

Safety and efficacy of imiquimod topical cream for the treatment of external genital or perianal HPV warts in children younger than 12 years of age have not been established.

Geriatric Precautions

Clinical studies evaluating safety and efficacy of topical imiquimod for the treatment of actinic keratosis or superficial basal cell carcinoma have included patients 65 years of age or older. Although no overall differences in efficacy or safety were observed between geriatric and younger patients and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

Mutagenicity and Carcinogenicity

Imiquimod was not mutagenic in several in vitro and in vivo tests, including the Ames test, mouse lymphoma assay, Chinese hamster ovary (CHO) chromosomal aberration assay, human lymphocyte chromosome aberration assay, SHE cell transformation assay, rat and hamster bone marrow cytogenetic tests, and mouse dominant lethal test.

There was no evidence of carcinogenicity when imiquimod doses up to 153 times the maximum recommended human dose (MRHD) (based on area under the plasma concentration-time curve [AUC] comparisons) were given orally to rats for 24 months. However, in a dermal carcinogenicity study in mice receiving topical application of imiquimod cream 0.3% for 24 months, there was an increase in the incidence of liver adenomas and carcinomas; an increased number of skin papillomas occurred in those receiving vehicle placebo. In addition, results of animal carcinogenicity studies indicate that topical imiquimod may enhance ultraviolet carcinogenicity and shorten the time to skin tumor formation; this effect is not necessarily dependent on phototoxic mechanisms.

Pregnancy, Fertility, and Lactation

Pregnancy

There was no evidence of embryotoxicity or teratogenicity when oral imiquimod was used in rats and rabbits at dosages 98 times the maximum recommended human dose (MRHD) (based on area under the plasma concentration-time curve [AUC] comparisons) or when IV imiquimod was used in rabbits at dosages 407 times the MRHD (based on AUC) or 1.5 times the MRHD (based on body surface area). When oral imiquimod dosages 577 times the MRHD (based on AUC) were used in rats, maternal toxicity occurred and adverse fetal effects included increased resorptions, decreased fetal body weight, delayed skeletal ossification, bent limb bones, and exencephaly, protruding tongues, and low-set ears. There are no adequate and controlled studies using imiquimod in pregnant women, and the drug should be used during pregnancy only when clearly needed.

Fertility

Studies in rats using oral imiquimod doses up to 87 times the MRHD (based on AUC) throughout mating, gestation, parturition, and lactation have not revealed evidence of impaired fertility.

Lactation

It is not known whether topically applied imiquimod is distributed into human milk. The drug should be used with caution in nursing women.

Pharmacokinetics

Absorption

Imiquimod is absorbed systemically following topical application to skin.

In adults with actinic keratosis who received topical imiquimod 5% cream 3 times weekly for 16 weeks, mean peak serum concentrations at the end of week 16 were approximately 0.1, 0.2, or 3.5 ng/mL in those treated on the face (12.5-mg doses), scalp (25-mg doses), or hands/arms (75-mg doses), respectively. Systemic exposure appeared to depend more on the surface area of the application site than on the total applied dose.

In patients with external genital and perianal human papillomavirus (HPV) warts who received topical imiquimod 5% cream (average dose 4.6 mg), mean peak serum concentrations were 0.4 ng/mL.

Distribution

It is not known whether imiquimod crosses the placenta following topical application.

It is not known whether imiquimod is distributed into milk following topical application.

Elimination

Studies using subcutaneous imiquimod indicate the drug has an apparent half-life of 2 hours. Following topical application, imiquimod appears to be retained in the skin for prolonged periods since the half-life is approximately 10 times greater than that reported following subcutaneous administration.

Following topical application to the skin in adults with actinic keratosis (75-mg doses 3 times weekly for 16 weeks), 0.08-0.15% of the dose is eliminated in urine as unchanged drug and metabolites.

Following topical application in patients with HPV warts, 0.11 or 2.41% of the dose is eliminated in urine as unchanged drug and metabolites in men or women, respectively.

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