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  • CLASSES

    Other Topical Agents Used In Viral Infections
    Other Topical Antineoplastics

    DEA CLASS

    Rx

    DESCRIPTION

    Topical medication
    Treatment of actinic keratosis, basal cell carcinoma, and external genital and perianal warts from HPV
    Preferred topical agent for external genital and perianal warts caused by HPV; can be self-administered

    COMMON BRAND NAMES

    Aldara, Zyclara

    HOW SUPPLIED

    Aldara/Imiquimod/Zyclara Topical Cream: 2.5%, 3.75%, 5%

    DOSAGE & INDICATIONS

    For the treatment of external genital and perianal warts (i.e., 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 (5% cream)
    Adults, Adolescents, and Children >= 12 years

    Apply a thin layer to the affected areas once daily 3 times per week (on nonconsecutive nights) just prior to sleep. The cream should be left on the skin for 6 to 10 hours and then washed off with mild soap and water. Continue therapy until there is a total clearance of warts or for a maximum of 16 weeks (median time to complete wart clearance is about 10 weeks). In a double-blind, placebo-controlled trial, eradication of baseline warts was observed in 50% of patients treated with 5% imiquimod cream and in 11% of patients who received vehicle cream. Although only limited data are available, the response rate may be lower in immunosuppressed patients (11% response rate reported in one study of HIV-infected patients) than in immunocompetent individuals.

    Infants† and Children < 12 years†

    Although not recommended by the manufacturer, guidelines suggest that imiquimod may be used in HIV-infected children with HPV. Guidelines recommend to apply a thin layer to the affected areas once daily 3 times per week (on nonconsecutive nights) just prior to sleep. The cream should be left on the skin for 6 to 10 hours and then washed off with mild soap and water. Continue therapy until there is a total clearance of warts or for a maximum of 16 weeks.

    Topical dosage (3.75% cream)

    NOTE: Safety and efficacy of the 3.75% cream have not been established in immunosuppressed persons.

    Adults, Adolescents, and Children >= 12 years

    Apply a thin layer to the affected areas once daily; only 1 packet or 1 full actuation of the pump may be administered per application. The cream should be applied prior to normal sleeping hours and left on the skin for approximately 8 hours. After 8 hours, wash off with mild soap and water. Continue therapy until there is a total clearance of warts or for a maximum duration of 8 weeks. In 2 clinical trials, complete clearance of baseline warts were observed in 27% and 29% of patients treated with 3.75% imiquimod cream and in 10% and 9% of patients who received vehicle cream.

    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).

    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.

    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 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 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 HIV-infected patients.
    Topical dosage
    Adults

    For HIV-infected patients, guidelines recommend the application of a 5% topical cream to lesions 3-times weekly for at least 21 to 28 days. The CDC recommends the cream be applied to lesions once daily for 5 consecutive days. A phase II randomized, double-blind, placebo-controlled trial of 124 non-HIV patients with herpes genitalis evaluated safety and efficacy of imiquimod 5% cream applied 1- to 3-times per week for 3 weeks. This study showed no statistically significant differences in comparison to placebo in time to first recurrence or in the annualized recurrence rate. However, another double-blind, placebo-controlled trial in 60 non-HIV men with herpes genitalis showed that imiquimod 1% cream applied twice daily resulted in significantly shorter mean lesion duration (p < 0.001) and a greater number of healed patients (p < 0.0001). Additional case reports in HIV-infected patients with resistant herpes genitalis using imiquimod 5% cream applied 2- to 3-times weekly have shown symptom resolution. A prospective, randomized, placebo-controlled trial studied imiquimod 5% cream in 47 non-HIV patients with recurrent herpes labialis. Time to first self-reported recurrence with imiquimod was 91 days as compared to 50 days with placebo (p = 0.018) and time to first clinically confirmed recurrence with imiquimod was 109 days vs. 50 days with placebo (p = 0.081). the study was terminated early due to severe local reactions in 5 patients.

    Adolescents

    For HIV-infected patients, guidelines recommend the application of a 5% topical cream to lesions 3-times weekly for at least 21 to 28 days. The CDC recommends the cream be applied to lesions once daily for 5 consecutive days.

    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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    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%.

    STORAGE

    Aldara:
    - Do not freeze
    - Store between 39 to 77 degrees F
    Zyclara:
    - Protect from freezing
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store upright

    CONTRAINDICATIONS / PRECAUTIONS

    Accidental exposure, benzyl alcohol hypersensitivity, ocular exposure, paraben hypersensitivity, surgery

    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.

    Human immunodeficiency virus (HIV) infection, immunosuppression

    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.

    Sunburn, sunlight (UV) exposure

    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.

    Contraceptive devices

    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.

    Occlusive dressing

    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.

    Pregnancy

    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 3528 +/- 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—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- to87-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. The CDC states that safety during pregnancy has not been established and recommends against use during pregnancy.

    Breast-feeding

    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.

    Children, infants, neonates

    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.

    ADVERSE REACTIONS

    Severe

    eczema vaccinatum / Delayed / 2.0-2.0
    atrial fibrillation / Early / 1.0-1.0
    erythema multiforme / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    capillary leak syndrome / Early / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    stroke / Early / Incidence not known
    seizures / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known

    Moderate

    erythema / Early / 58.0-100.0
    skin erosion / Delayed / 4.0-66.0
    skin ulcer / Delayed / 4.0-66.0
    lymphadenopathy / Delayed / 2.0-3.0
    chest pain (unspecified) / Early / 1.0-1.0
    edema / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    palpitations / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    urinary retention / Early / Incidence not known
    dysuria / Early / Incidence not known
    depression / Delayed / Incidence not known
    paresis / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    anemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known

    Mild

    xerosis / Delayed / 88.0-93.0
    pruritus / Rapid / 3.0-32.0
    infection / Delayed / 1.0-15.0
    skin irritation / Early / 1.0-10.0
    rash / Early / 1.0-10.0
    vesicular rash / Delayed / 2.0-9.0
    headache / Early / 2.0-8.0
    sinusitis / Delayed / 2.0-7.0
    back pain / Delayed / 1.0-4.0
    fatigue / Early / 1.0-4.0
    nausea / Early / 1.0-4.0
    rhinitis / Early / 3.0-3.0
    fever / Early / 0-3.0
    dizziness / Early / 0-3.0
    arthralgia / Delayed / 1.0-3.0
    diarrhea / Early / 1.0-3.0
    anorexia / Delayed / 0-3.0
    cheilitis / Delayed / 2.0-2.0
    dyspepsia / Early / 1.0-2.0
    cough / Delayed / 0-2.0
    alopecia / Delayed / 1.0-1.0
    pharyngitis / Delayed / 1.0-1.0
    anxiety / Delayed / 0-1.0
    myalgia / Early / 1.0-1.0
    vomiting / Early / 0-1.0
    skin hyperpigmentation / Delayed / Incidence not known
    skin hypopigmentation / Delayed / Incidence not known
    skin discoloration / Delayed / Incidence not known
    chills / Rapid / Incidence not known
    syncope / Early / Incidence not known
    insomnia / Early / Incidence not known
    agitation / Early / Incidence not known
    lethargy / Early / Incidence not known
    abdominal pain / Early / Incidence not known

    DRUG INTERACTIONS

    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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 3528 +/- 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—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- to87-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. The CDC states that safety during pregnancy has not been established and recommends 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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.

    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.