IMIQUIMOD (Generic for ZYCLARA)

Imiquimod is a topical agent for the treatment of actinic keratosis, basal cell carcinoma, and external genital and perianal warts (i.e., condylomata acuminata) caused by human papillomavirus (HPV). Like podofilox, imiquimod can be self-administered by the patient, whereas other treatments for condyloma acuminata (e.g., intralesional interferon alfa, podophyllum resin, trichloroacetic acid) must be administered by a health-care provider. Imiquimod, like other currently available therapies for exophytic genital and perianal warts, does not eradicate HPV or affect the natural history of HPV infection. Despite destruction of HPV warts, latent or subclinical HPV infection can persist and recurrence of visible warts is common. Imiquimod cream was granted final FDA approval for the treatment of condylomata acuminata in March 1997. In March 2004 and July 2004, the FDA approved imiquimod cream for the treatment of actinic keratosis and basal cell carcinoma, respectively.

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Topical Administration
-For topical use to external areas only; avoid ocular exposure.
-The cream is usually applied at bedtime.
-Wash hands before and after applying cream.
-If using the 3.75% pump, prime the pump prior to the first use by repeatedly depressing the actuator until cream is dispensed; it is not necessary to repeat the priming process during the treatment period.
-A thin layer of the cream should be applied topically with the fingers; the cream should be massaged gently into the affected areas until no longer visible.
-Partially used packets should be discarded and not reused.

For use in Genital/Perianal Warts
-The 5% cream should be applied 3 times weekly (e.g., Monday, Wednesday, Friday or Tuesday, Thursday, Saturday) until total clearance or for a maximum of 16 weeks.
-The 3.75% cream is applied once daily until total clearance or for up to 8 weeks. Patients should not be prescribed more than 56 packets (2 boxes), two 7.5 gram pumps, or one 15 gram pump for the treatment course.
-Apply imiquimod cream to external genital/perianal warts. The technique for proper administrated should be demonstrated by the prescriber to maximize the benefit of therapy.
-Apply cream prior to normal sleeping hours. The 5% cream should be left on the skin for 6-10 hours and the 3.75% cream should be left on skin for approximately 8 hours. Wash off with mild soap and water (usually on wakening).
-In females, application in the vagina is considered internal and should be avoided. Take care if applying 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.
-Uncircumcised males treating warts under the foreskin should pull back the foreskin and clean the area daily to help avoid penile skin reactions.
-Occlusive dressings should not be used. However, non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions.

For use in Actinic Keratosis
-Twice weekly application of the 5% cream should be separated by 3-4 days (e.g., Monday and Thursday or Tuesday and Friday).
-The 3.75% and 2.5% cream is applied for two 2-week treatment cycles separated by a 2-week no-treatment period.
-Patients should not be prescribed more than 36 packets (3 boxes) of the 5% cream for the 16-week treatment period. Do not prescribe more than 56 packets (2 boxes) of the 3.75% or 2.5% cream, two 7.5 gram pumps (3.75% cream), or one 15 gram pump (3.75% cream) for the total 2-cycle treatment course.
-Patients should apply no more than one packet of the 5% imiquimod cream, 2 packets of the 3.75% or 2.5% cream, or 2 full actuations of the 3.75% pump to the contiguous treatment area at each application.
-Before applying the cream, wash the treatment area with mild soap and water and allow the area to dry thoroughly (at least 10 minutes).

-Apply cream prior to normal sleeping hours, and leave on skin for approximately 8 hours, after which time the cream should be removed by washing the area with mild soap and water.
-Avoid contact with the lips, eyes, and nostrils.

For use in Superficial Basal Cell Carcinoma
-Patients should not be prescribed more than 3 boxes for the 6-week treatment period.
-Prior to application of imiquimod cream, wash the treatment area with mild soap and water and allow the area to dry thoroughly.
-Apply cream using sufficient amount to cover the treatment area including 1 cm of skin surrounding the area. The technique for proper administrated should be demonstrated by the prescriber to maximize the benefit of therapy.
-The cream should be left on the skin for about 8 hours and then washed off with mild soap and water (usually on wakening).
-The amount of cream to be used is dependent upon the size of the area to be treated:
-For target tumor diameter of 0.5 to < 1 cm, use a 4 mm droplet of imiquimod cream 5%.
-For target tumor diameter of >= 1 to < 1.5 cm, use a 5 mm droplet of imiquimod cream 5%.
-For target tumor diameter of >= 1.5 to 2 cm, use a 7 mm droplet of imiquimod cream 5%.

The most common adverse events associated with use of imiquimod are local skin reactions and application site reactions such as itching, burning, stinging, induration, tenderness, erythema, papule, soreness, bleeding, swelling, skin irritation, pain, rash (unspecified), cellulitis, and excoriation. Most of these application site reactions occurred in less than 5% of patients with the exception of pruritus, which occurred in 16% to 32% of imiquimod 5% recipients as compared with 3% to 4% of the 2.5% or 3.75% cream recipients. Intense local inflammatory reactions including skin weeping or erosion can occur after few applications of imiquimod and may necessitate a rest period of several days. In trials, 7% to 32% needed a rest period. Local skin reactions in the treatment area included erythema (58% to 100%), scabbing/crusting (79% to 93%), edema (12% to 78%), skin erosion/skin ulcer (4% to 66%), weeping/exudate (22% to 51%), flaking/scaling/xerosis (88% to 93%), vesicles/vesicular rash (2% to 9%), and induration (7% to 84%). Other adverse reactions reported include eczema (2%), alopecia (1%), papules (2%), sensitivity, application site swelling, cheilitis (2%), and dermatitis. Tingling at the application site, exfoliative dermatitis, erythema multiforme, skin hyperpigmentation (possibly permanent), skin hypopigmentation (possibly permanent skin discoloration), and hypertrophic scar have all been noted in postmarketing reports. Angioedema has also been noted postmarketing and may be difficult to differentiate from a local skin reaction.Uncircumcised males treating warts under the foreskin should pull back the foreskin and clean the area daily to help avoid severe penile skin reactions, like stricturing. Adverse reactions are more frequent and intense if imiquimod 5% cream is administered once daily rather than the currently recommended 3-times weekly regimen for the treatment of external genital warts. Also, avoid use of multiple imiquimod products on the same area because of a potential increased risk for and severity of local skin reactions. If a severe local reaction occurs, the cream should be removed by washing with mild soap and water. Non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions. Treatment can be resumed after the skin reaction has subsided.

Fever (<= 3%), rigors (1%), influenza-like symptoms (< 1% to 4%), lymphadenopathy (2-3%), and chills were noted with imiquimod receipt during clinical trials. Lymphadenopathy resolved in all patients by 4 weeks after treatment completion. Of note, fever and chills may be flu-like signs; consider an interruption of dosing and an assessment of the patient. Infectious and inflammatory adverse events associated with imiquimod during clinical trials included upper respiratory tract infection (3-15%), sinusitis (2-7%), urinary tract infection (1-3%), general viral infection (1%), rhinitis (3%), pharyngitis (1%), fungal infection (2-11%), herpes simplex (3%), and herpes zoster. Treatment site infections were noted in 1-3.23% of patients and required a rest period and antibiotics. Tinea cruris was noted during post-marketing reports.

Cardiovascular adverse events reported during imiquimod clinical trials included atrial fibrillation (1%) and chest pain (unspecified) (1%). Other adverse events noted in post-marketing reports included capillary leak syndrome, heart failure, cardiomyopathy, pulmonary edema, arrhythmia exacerbation (sinus tachycardia, supraventricular tachycardia (SVT), atrial fibrillation, palpitations), ischemia, myocardial infarction, and syncope.

Proteinuria, dysuria, and urinary rentention have been noted in post-marketing reports. Imiquimod can cause severe local inflammatory reactions of the female external genitalia, which can lead to vulvar swelling. Severe vulvar swelling can cause urinary retention. Dosing should be interrupted or discontinued for severe vulvar swelling.

Central nervous system and psychiatric adverse events reported during imiquimod clinical trials included headache (2-8%), dizziness (< 1% to 3%), and anxiety (< 1% to 1%). Other neuropsychiatric events noted during post-marketing reports included agitation, cerebrovascular accident (stroke), convulsions/seizures (including febrile convulsions), depression, insomnia, multiple sclerosis aggravation, paresis, and suicide.

Adverse events reported during imiquimod clinical trials included fatigue (1-4%), lethargy, back pain (1-4%), arthralgia (1-3%), and myalgia (1%). Of note, flu-like signs and symptoms may include fatigue, myalgias, arthralgias, or malaise; consider an interruption of dosing and an assessment of the patient for flu-like symptoms.

Gastrointestinal adverse events reported during imiquimod clinical trials included diarrhea (1-3%), vomiting (< 1% to 1%), dyspepsia (1-2%), nausea (1-4%), and anorexia (<= 3%). Abdominal pain and abnormal liver function were noted in post-marketing reports. Of note, nausea may be associated with flu-like symptoms; consider an interruption of dosing and an assessment of the patient for flu-like symptoms.

Imiquimod may cause a new primary malignancy. Squamous cell carcinoma was reported in 4% of patients during imiquimod clinical trials as compared with 2% of vehicle recipients. Lymphoma has been noted in postmarketing reports.

Cough was reported in < 1% to 2% of patients during imiquimod clinical trials. Dyspnea was noted in post-marketing reports.

Pancytopenia, anemia, leukopenia, and thrombocytopenia (including idiopathic thrombotic thrombocytopenic purpura (TTP)) have all been noted in post-marketing reports of imiquimod.

Thyroiditis and Henoch-Schonlein purpura syndrome, a systemic vasculitis, have been noted in post-marketing reports for imiquimod. Cautious use of imiquimod is advised for patients with pre-existing autoimmune conditions because imiquimod activates immune cells.

There are no known absolute contraindications to the use of imiquimod. The cream contains benzyl alcohol and parabens; use with caution in patients with known benzyl alcohol hypersensitivity or paraben hypersensitivity. Mild to moderate local skin reactions to the drug are common. Should a severe local skin reaction occur, the cream should be removed. Wash the area with mild soap and water. Treatment with imiquimod can be resumed after the skin reaction has subsided. There is no clinical experience with imiquimod cream therapy immediately following the use of other cutaneously applied drugs; therefore, imiquimod cream administration is not recommended until the skin is healed from any previous drug treatment or surgery. Imiquimod is for topical external use as directed only; avoid accidental exposure to other areas, including nasal, lip, or ocular exposure. Imiquimod cream should only be used for the treatment of biopsy-confirmed superficial basal cell carcinoma in immunocompetent adults, with a maximum tumor diameter of 2 cm on the trunk (excluding the anogenital skin), neck, or extremities (excluding the hands and feet). Safe and effective use of Imiquimod cream for other types of basal cell carcinoma, including fibrosing or sclerosing, Basal Cell Nevus Syndrome, or xeroderma pigmentosum has not been established. Safety and efficacy have not been established for imiquimod cream in repeated treatment of actinic keratosis (i.e., > 1 treatment course in the same 25 cm2 area) or superficial basal cell carcinoma. Additionally, the safety of imiquimod cream applied to areas of skin > 25 cm2 (e.g., 5 cm x 5 cm) for the treatment of actinic keratosis has not been established.

Imiquimod has not been evaluated for the treatment of internal urethral, intra-vaginal, cervical, or rectal human papilloma viral disease and is not recommended for these conditions. The safety and efficacy of imiquimod cream in patients with immunosuppression have not been established. Although only limited data are available, the response rate to imiquimod cream may be lower in patients with immunosuppression or human immunodeficiency virus (HIV) infection than in immunocompetent individuals.

Sunlight (UV) exposure, including artificial sunlight exposure, should be avoided or minimized during treatment of actinic keratosis with imiquimod because of a concern for increasing the risk for sun sensitivity. Patients should be counseled to wear protective clothing (hat) when using imiquimod cream. Patients with sunburn should be advised not to use imiquimod cream until fully recovered. Patients who may have considerable sun exposure (e.g., due to occupation, those with inherent sensitivity to sunlight) should exercise caution when using imiquimod cream. Phototoxicity has not been adequately addressed for imiquimod cream. The enhancement of ultraviolet carcinogenicity is not necessarily dependent upon phototoxic mechanisms. Despite the absence of observed phototoxicity in humans, imiquimod cream shortened the time to skin tumor formation in an animal photo-carcinogenicity study.

Imiquimod cream may weaken barrier contraceptive devices such as condoms and vaginal diaphragms. Therefore, reliance on these devices for birth control is not recommended during treatment of genital/perianal warts.

Due to the potential for enhanced systemic absorption of imiquimod, an occlusive dressing should not be applied to the treatment area. However, non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions.

Imiquimod is classified as FDA pregnancy risk category C. During the topical imiquimod clinical program, 10 women who were treated with imiquimod cream became pregnant. Pregnancy outcome information is available for 3 of the 5 women who chose to continue their pregnancies. All three women delivered full term, normal infants (manufacturer's data on file). Live infants (mean weight of 3,528 +/- 482 g) with no major malformations or other adverse effects were also delivered by 2 women who used imiquimod in the first trimester, by 1 woman who used it in the second trimester, by 2 women who used it in the second and third trimesters, and by 2 women who used it in the third trimester. Use of the 5% cream ranged from three times a week to daily, and the mean duration of use was 5 weeks (range, 1 to 10 weeks). Some animal studies have demonstrated fetal effects (e.g., increased resorption, decreased fetal weights, delays in ossification, bent limb bones, and exencephaly) at doses 163- to 577-times the maximum recommended human dose (MRHD) based on area under the curve (AUC) comparisons (in the presence of maternal toxicity) and at a dose 25- to 87-times the MRHD based on AUC comparisons without maternal toxicity. Imiquimod was not found to be teratogenic in rat or rabbit teratology studies. There are no adequate and well-controlled studies in pregnant women; use during pregnancy if the potential benefit justifies the potential risk to the fetus. Guidelines state that safety during pregnancy has not been established and recommend against use during pregnancy.

Data are limited regarding use of imiquimod during breast-feeding, and its excretion into human milk is unknown. Based on the drugs low molecular weight (240) and prolonged half-life (24-29 hours), excretion in breast milk is possible; however, because only minimal amounts of the drug are systemically absorbed through the skin, significant presence in breast milk is considered unlikely. The manufacturer advises caution when administering to lactating women. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

The efficacy of the imiquimod cream has not been established in neonates, infants, or children < 12 years of age. Two randomized, vehicle-controlled double-blind studies of 702 pediatric patients (age 2-12 years; median age 5 years) with molluscum contagiosum failed to demonstrate efficacy of imiquimod 5% over placebo. Study participants applied imiquimod 5% or vehicle three times weekly for up to 16 weeks. The complete clearance rate in the first study was 24% in the imiquimod group vs. 26% in the vehicle group. The complete clearance rate in the second study was 24% in the imiquimod group vs. 28% in the vehicle group. The safety and efficacy of imiquimod cream for the treatment of actinic keratosis or superficial basal cell carcinoma in neonates, infants, children, or adolescents < 18 years have not been established. In addition, during use of imiquimod in the genital area, dysuria and the inability to void secondary to severe local reactions have been reported in pediatric female patients.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human papillomavirus (HPV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: herpes simplex virus type 1, herpes simplex virus type 2
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of external genital and perianal warts (condylomata acuminata) due to human papillomavirus (HPV) infection:
NOTE: Imiquimod 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.
Topical dosage (3.75% cream):
Adults: Apply a thin layer topically to the wart(s) once daily at bedtime until complete clearance of all warts or for a maximum of 8 weeks. Leave cream on skin for about 8 hours, then remove. Max: 0.25 g cream/day.
Children and Adolescents 12 to 17 years: Apply a thin layer topically to the wart(s) once daily at bedtime until complete clearance of all warts or for a maximum of 8 weeks. Leave cream on skin for about 8 hours, then remove. Max: 0.25 g cream/day.
Topical dosage (5% cream):
Adults: Apply a thin layer topically to the wart(s) 3 times weekly at bedtime on nonconsecutive nights until complete clearance of all warts or for a maximum of 16 weeks. Leave cream on skin for 6 to 10 hours, then remove.
Children and Adolescents 12 to 17 years: Apply a thin layer topically to the wart(s) 3 times weekly at bedtime on nonconsecutive nights until complete clearance of all warts or for a maximum of 16 weeks. Leave cream on skin for 6 to 10 hours, then remove.
Infants* and Children* 1 month to 11 years: Apply a thin layer topically to the wart(s) 3 times weekly at bedtime on nonconsecutive nights until complete clearance of all warts or for a maximum of 16 weeks. Leave cream on skin for 6 to 10 hours, then remove.

For the treatment of actinic keratosis (AK):
-for the treatment of clinically typical, non-hyperkeratotic, non-hypertrophic actinic keratosis (AK) on the face or scalp in immunocompetent adults:
Topical dosage (5% cream):
Adults: Apply a thin layer once daily 2 times per week (each dose 3 to 4 days apart) just prior to sleep 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 cm2 (e.g., 5 cm x 5 cm). Imiquimod cream should be applied to the entire treatment area (e.g., the forehead, scalp, or 1 cheek). The cream should be on the skin for approximately 8 hours and then washed off with mild soap and water. 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. In a pilot study, treatment with imiquimod 5% cream 3 times weekly resulted in successful clearing of all lesions. Two manufacturer-sponsored double-blind, randomized, placebo-controlled trials involving 436 patients with multiple AKs have now been completed; in these studies, imiquimod cream was applied twice weekly for 16 weeks. At 8 weeks post-treatment, 50% of those treated had at least an 83% reduction in the number of AK lesions counted at baseline vs. 0% in the placebo group. Complete clearance of AKs was seen in 45% of those treated (vs. 3% in placebo group).
Infants, Children, and Adolescents: Safety and efficacy have not been established.
-for the treatment of clinically typical visible or palpable actinic keratosis (AK) on the full face or balding scalp in immunocompetent adults:
Topical dosage (2.5% and 3.75% cream):
Adults: Apply a thin layer once daily before bedtime to the affected area for two 2-week treatment cycles separated by a 2-week no-treatment period. Up to 2 packets or 2 full actuations of the pump may be applied per application. The cream should be on the skin for approximately 8 hours and then washed off with mild soap and water.
Infants, Children, and Adolescents: Safety and efficacy have not been established.

For the treatment of molluscum contagiosum*:
Topical dosage:
Adults, Adolescents, and Children >= 9 years: In a double-blind, placebo-controlled study (n = 100, age range 9 to 27 years), imiquimod 1% cream was applied topically 3 times per day for 5 consecutive days each week. Treatment duration was 4 weeks. Use resulted in a cure rate of 82% vs. a 16% cure rate in placebo-treated patients.

For the treatment of basal cell carcinoma (BCC):
-for the treatment of biopsy-confirmed, primary superficial BCC in immunocompetent adults who have a maximum tumor diameter of 2 cm that is located on the trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet):
NOTE: The safety and efficacy for the treatment of other types of BCC (e.g., nodular and morpheaform types) or basal cell nevus syndrome or xeroderma pigmentosum have not been established.
Topical dosage (5% cream):
Adults: Apply once daily prior to bedtime 5 times per week (e.g., Monday through Friday) for 6 weeks; leave cream on for approximately 8 hours. Additional rest time up to several days may be needed due to local skin reactions. The size of cream droplet (amount of cream) per dose depends on the target tumor diameter as follows: 0.5 to less than 1 cm, apply 4 mm diameter droplet (10 mg); 1 to less than 1.5 cm, apply 5 mm diameter droplet (25 mg); and 1.5 to 2 cm, apply 7 mm diameter droplet (40 mg). The treatment area should include a 1 cm margin of skin around the tumor. The safety and efficacy of a repeat course have not been established. The complete composite clearance rates (defined as the proportion of subjects at the 12-week posttreatment visit who were complete responders to treatment) were 75% in patients who received imiquimod once daily 5 times per week and 73% in patients who received imiquimod once daily 7 times per week. The complete composite clearance rates were significantly higher with topical imiquimod compared with vehicle only (p = 0.001). Of note, dosing was not extended beyond the 6-week treatment period to make up for missed doses during rest periods due to toxicity.

For the treatment of lentigo maligna*:
Topical dosage (5% cream):
Adults: In a small single institutional trial, 30 patients were treated with imiquimod 5% cream applied topically once daily for 3 months. Of the 28 evaluable patients, 26 (93%) were complete responders and 2 were treatment failures. Over 80% of the 28 subjects completing treatment and have been followed for longer than 1 year with no relapses. In a separate case study, 12 patients were treated with imiquimod 3 times weekly for 6 weeks. In the absence of an inflammatory response, patients increased application to once daily. Ten of 12 patients cleared with no relapse after a median follow-up of 6 months.

For the treatment of acyclovir-resistant mucocutaneous herpes simplex virus infection*, including herpes genitalis*, in persons living with HIV:
Topical dosage:
Adults: Apply 5% topical cream to lesions 3 times weekly for at least 21 to 28 days as an alternative.
Adolescents: Apply 5% topical cream to lesions 3 times weekly for at least 21 to 28 days as an alternative.

For the treatment of vulvar intraepithelial neoplasia (VIN)*:
Topical dosage (5% cream):
Adults: In a double-blind, placebo-controlled study, 52 patients with grade 2 or 3 vulvar intraepithelial neoplasia were randomly assigned to twice weekly applications of either imiquimod 5% cream or placebo for 16 weeks. At 20 weeks (4 weeks after the end of treatment), a reduction in lesion size of at least 25% was observed in 21 of 26 patients (86%) in the imiquimod group vs. none of those treated in the placebo group (p < 0.001). Nine patients in the imiquimod group achieved a complete response at week 20, and remained free of disease at 12 months. Of 50 patients who tested positive for HPV DNA, 15 in the imiquimod group and 2 in the placebo group experienced clearing of HPV from the lesion. There was a strong association between viral clearance and histologic regression (p < 0.001). Pruritus and pain were also reduced in the imiquimod group.

Maximum Dosage Limits:
-Adults
2 packets of 5% cream (25 mg imiquimod) per application; 2 packets of 3.75% cream (18.8 mg imiquimod) per application; 2 pump actuations of 3.75% cream (17.6 mg imiquimod) per application; 2 packets of 2.5% cream (12.5 mg imiquimod) per application.
-Geriatric
2 packets of 5% cream (25 mg imiquimod) per application; 2 packets of 3.75% cream (18.8 mg imiquimod) per application; 2 pump actuations of 3.75% cream (17.6 mg imiquimod) per application; 2 packets of 2.5% cream (12.5 mg imiquimod) per application.
-Adolescents
2 packets of 5% cream (25 mg imiquimod) per application; 1 packet of 3.75% cream (9.4 mg imiquimod) per application; 1 pump actuation of 3.75% cream (8.8 mg imiquimod) per application.
-Children
>= 12 years: 2 packets of 5% cream (25 mg imiquimod) per application; 1 packet of 3.75% cream (9.4 mg imiquimod) per application; 1 pump actuation of 3.75% cream (8.8 mg imiquimod) per application.
< 12 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Podofilox: (Minor) While no drug interactions have been reported with imiquimod, there is no clinical experience with imiquimod cream therapy immediately following the treatment of genital/perianal warts with other cutaneously applied drugs, such as podofilox. Therefore, imiquimod cream administration is not recommended until skin is healed from any previous topical drug treatments or surgery.

Podophyllum: (Minor) While no drug interactions have been reported with imiquimod, there is no clinical experience with imiquimod cream therapy immediately following the treatment of genital/perianal warts with other cutaneously applied drugs, such as podophyllum resin. Therefore, imiquimod cream administration is not recommended until skin is healed from any previous topical drug treatments or surgery.

The exact mechanism of action of imiquimod is unknown. The manufacturer classifies imiquimod as an 'immune response modifier.' A human study revealed that imiquimod induces mRNA encoding cytokines including interferon-alfa 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. Animal data reveal that imiquimod induces cytokines such as interferon-alfa, tumor necrosis factor-alpha, and interleukins 1, 6, and 8.
-Genital or perianal warts: Exophytic genital and perianal warts are usually caused by human papillomavirus (HPV) types 6 or 11.Wart clearance was associated with tissue production of interferon-alpha, -beta, and -gamma and tumor necrosis factor-alpha. Clinically, the onset of effect is gradual, with most patients (83%) showing some response to treatment in 4 weeks. Median time to complete clearance was 8 weeks for females and 12 weeks for males; however, wart clearing may take up to 16 weeks. As with most common treatments, imiquimod reduces but does not eliminate the HPV load, even if acetowhitened subclinical lesions are targeted, and thus warts may reappear. The approach offers symptomatic relief, but this relief is generally only temporary. In animal models, imiquimod demonstrates antiviral and antitumor activity. The drug does not possess antiviral or antitumor activity in vitro and the effect of topical therapy on transmission of HPV is unknown.
-Actinic keratosis (AK) and other cancerous or pre-cancerous skin lesions: In a study of 18 patients with AK, at week 2 increases from baseline in biomarker levels were reported for CD3, CD4, CD8, CD11c, and CD68 for patients treated with imiquimod cream as compared to vehicle. The clinical relevance of these findings is unknown. In a separate study, a dense mononuclear infiltrate was noted surrounding imiquimod-treated basal cell carcinomas, which was determined to be primarily T-helper lymphocytes. However, a significant portion of these cells also stained positive for CD56 indicating the presence of natural killer cells. Imiquimod's antitumor effects appear mediated by up regulation of local alpha interferon levels and that natural killer cells may be responsible for tumor response.

Imiquimod is applied topically. In a small study of 12 patients with genital/perianal warts following an average applied dose of 4.6 mg, mean urine recoveries of imiquimod and metabolites combined over the entire course of treatment were 0.11% in males and 2.41% in females (expressed as a percent of the estimated applied dose). In patients with actinic keratosis who applied imiquimod topically 3-times weekly for 16 weeks, mean urinary recoveries of imiquimod and metabolites combined were 0.08% and 0.15% of the applied dose in the group using 75 mg for males and females, respectively.


-Route-Specific Pharmacokinetics
Topical Route
Percutaneous absorption of imiquimod is minimal. A mean peak drug concentration of 0.4 ng/ml was observed in a small study of 12 patients with genital/perianal warts following an average applied dose of 4.6 mg. In patients with actinic keratosis who applied imiquimod 5% cream topically 3-times weekly for 16 weeks, the mean peak drug concentrations at the end of week 16 were approximately 0.1, 0.2, and 3.5 ng/mL for applications to face (12.5 mg imiquimod), scalp (25 mg imiquimod), and hands/arms (75 mg imiquimod), respectively. After up to 3 weeks of dosing with the 3.75% cream (18.75 mg/day applied to the face and scalp) in 17 patients with actinic keratosis, the mean peak serum imiquimod concentration was 0.323 ng/mL with a median Tmax of 9 hours after dosing. It appears that systemic exposure may be more dependent upon surface area of application than amount of applied dose. The half-life of the 3.75% cream was 29.3 +/- 17 hours at the end of the study; therefore, steady-state concentrations are anticipated to occur by day 7 with once daily dosing. The apparent half-life of the 5% cream was about 10-times greater with topical dosing than the 2 hour apparent half-life seen following subcutaneous dosing, suggesting prolonged retention in the skin.


-Special Populations
Pediatrics
In 22 children, age 2 to 12 years, with extensive molluscum contagiosum affecting at least 10% of total body surface area, systemic absorption of imiquimod was observed following application 3 times per week for 4 weeks. The dose applied (i.e., 1, 2, or 3 packets per dose) was determined by the size of the treatment area and the patients weight. Children aged 2 to 5 years received doses of 12.5 mg (1 packet) to 25 mg (2 packets) per dose and had median multiple-dose peak serum drug levels of approximately 0.2 or 0.5 ng/mL, respectively. Children aged 6 to 12 years received doses of 12.5 mg, 25 mg, or 37.5 mg (3 packets) per dose and had median multiple-dose peak serum drug levels of approximately 0.1, 0.15, or 0.3 ng/ml, respectively. At the end of week 4, the median peak serum drug concentration was between 0.26 and 1.06 ng/ml.