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.[29485] [42124]

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.[29485] [42124]

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.[29485] [42124]

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.[29485]

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.[29485] [42124]

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.[29485] [42124]

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.[29485] [42124]

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.[29485] [42124]

Cough was reported in < 1% to 2% of patients during imiquimod clinical trials. Dyspnea was noted in post-marketing reports.[29485] [42124]

Pancytopenia, anemia, leukopenia, and thrombocytopenia (including idiopathic thrombotic thrombocytopenic purpura (TTP)) have all been noted in post-marketing reports of imiquimod.[29485] [42124]

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.[29485][42124]

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.[29485] 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.[66938]

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.[66938] 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).[32990] 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.[29485] [42124] Guidelines state that safety during pregnancy has not been established and recommend against use during pregnancy.[66938]

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.[42124] [29485]

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.