Each gram of Aldara contains imiquimod 50 mg in an off-white, oil-in-water vanishing cream base consisting of isostearic acid, cetyl alcohol, stearyl alcohol, white soft paraffin, polysorbate 60, sorbitan monostearate, glycerol, xanthan gum, purified water, benzyl alcohol, methyl-hydroxybenzoate and propyl-hydroxy-benzoate.
Imiquimod is 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine. It has a molecular formula of C14H16N4 and a molecular weight of 240.3. It is odourless, white to off-white crystalline solid.
Pharmacology: Pharmacodynamics: Imiquimod is an immune response modifier. It has no direct antiviral activity in cell culture. A mechanism of action study in 22 patients with genital/perianal warts shows that imiquimod induces cytokines including interferon-α at the treatment site. In addition, HPV E7 and L1 mRNA as well as HPV DNA are significantly decreased following treatment. However, the clinical relevance of these findings is unknown.
Clinical Studies: In a double-blind, placebo-controlled clinical trial, Aldara applied 3 times a week for treatment of genital and perianal warts had wart clearance that were statistically significantly greater than the placebo control. The percentage of patients achieving total clearance was 77% for females and 40% for males. The percentage of patients achieving partial wart area (>50%) reduction was 91% for females and 74% for males. The median baseline wart area was 69 mm2 (range 8-5225 mm2). Visible wart changes occurred as early as 4 weeks and some patients required 16 weeks. The median time to total wart clearance was 10 weeks. In another study, Aldara applied daily, 59% of the males and 84% of the females achieved total clearance of their genital/perianal warts. A low percentage (6-23%) of the patients who achieved total clearance of their warts experienced a recurrence of their warts during the 12-week follow-up period. In 2 studies, some patients achieved total clearance or additional reduction in wart area during a 4-week treatment-free observation period following Aldara treatment. Thus, some patients with wart tissue remaining after Aldara treatment may continue to show clearing of their warts.
Pharmacokinetics: Less than 0.9% of a topically applied single dose of radiolabelled imiquimod was absorbed through the skin of human subjects. The small amount of imiquimod which was absorbed into the systemic circulation was promptly excreted by both urinary and faecal routes at a mean ratio of approximately 3:1. No quantifiable levels (>5 ng/mL) of imiquimod were detected in serum after single or multiple topical doses.
The data defining systemic absorption of imiquimod are limited by the use of bioanalytical method with a 5 ng/mL lower limit or quantitation. Systemic exposure (percutaneous penetration) was calculated from the recovery of carbon-14 (14C) imiquimod in urine and faeces.
Treatment of external genital and perianal warts/condyloma acuminata in adults.
Aldara cream is to be applied 3 times a week, prior to normal sleeping hours, and left on the skin for 6-10 hrs. Examples of 3 times a week application schedules are: Monday, Wednesday, Friday; or Tuesday, Thursday, Saturday application prior to sleeping hours. Aldara treatment should continue until there is clearance of the genital/perianal warts or for a maximum of 16 weeks.
Local skin reactions (erythema) at the treatment site are common. A rest period of several days may be taken if required by the patient's discomfort or severity of the local skin reaction. Treatment may resume once the reaction subsides. Non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions.
Administration: A thin layer is to be applied to the wart area and rubbed in until the cream is no longer visible. Aldara is packaged in single-use packets which contain sufficient cream to cover a wart area of up to 20 cm2; use of excessive amounts of cream should be avoided. Handwashing before and after cream application is recommended. The application site is not to be occluded. During the 6-10 hrs treatment period, showering or bathing should be avoided. Following the treatment period, Aldara cream should be removed by washing the treated area with mild soap and water.
Overdosage of Aldara in humans is unlikely due to minimal percutaneous absorption. Animal studies reveal a dermal lethal dose of >5000 mg/kg. Persistent topical overdosing of Aldara could result in severe local skin reactions. These usually subside within 2 weeks of discontinuation.
Following accidental ingestion of a single 200 mg imiquimod (corresponds to the content of approximately 16 sachets), nausea, emesis, headache, and fever can occur. The most clinically serious adverse event reported following multiple oral imiquimod doses of >200 mg was hypotension, which resolved following oral or IV fluid administration.
Hypersensitivity to imiquimod or to any excipients of Aldara.
Aldara has not been evaluated for treatment of internal genital warts and should not be used to treat urethral, intravaginal, cervical, rectal or intra-anal warts due to unknown local tolerance and potential systemic absorption.
Local skin reactions eg, erythema, erosion, excoriation/flaking and oedema are common. Most skin reactions are mild to moderate. These reactions may be due to the pharmacological response of the body's immune system to Aldara. Should severe local skin reactions occur, the cream should be removed by washing the treatment area with mild soap and water. Treatment with Aldara can be resumed after the skin reaction has subsided. The use of an occlusive dressing is not recommended with Aldara. Higher than recommended doses may lead to increased local skin reactions. Uncircumcised males treating warts under the foreskin should retract the foreskin and clean the area daily.
There is no clinical experience with Aldara therapy immediately following the treatment of genital/perianal warts with other cutaneously applied drugs; therefore, Aldara administration is not recommended until genital/perianal tissue is healed from any previous drug. Aldara has been applied to traumatized genital skin following wart ablation by electrocautery or cryotherapy in two pilot studies and Aldara did not prolong wound healing in these patients.
Aldara, as an immune response modifier, has been shown to induce mRNA for IL-8 and has the potential to exacerbate inflammatory conditions of the skin.
The effect of Aldara on the transmission of genital/perianal warts is unknown. Sexual (genital, anal, oral) contact should be avoided while the cream is on the skin. Aldara may weaken condoms and vaginal diaphragms. Therefore, concurrent use is not recommended.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Imiquimod was without effect in a series of 8 different mutagenicity assays including Ames, mouse lymphoma, CHO chromosome aberration, human lymphocyte chromosome aberration, SHE cell transformation, rat and hamster bone marrow cytogenetics and mouse dominant lethal test. Orally administered imiquimod is neither mutagenic nor teratogenic in rats and rabbits. Imiquimod applied dermally was not carcinogenic in mice. Daily oral administration of imiquimod to rats, at doses up to 8 times the recommended human dose on a mg/m2 basis throughout mating, gestation, parturition and lactation, demonstrated no impairment of reproduction.
Use in Pregnancy: Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. Imiquimod was not found to be teratogenic in rat or rabbit teratology studies. In rats at a high maternally toxic dose (28 times human dose on a mg/m2 basis), reduced pup weights and delayed ossification were observed. In developmental studies with offspring of pregnant rats treated with imiquimod (8 times human dose), no adverse effects were demonstrated.
Use in Lactation: It is not known whether topically applied imiquimod is excreted in breast milk.
Use in Children: Safety and efficacy in patients <18 years have not been established.
Pregnancy: Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. Imiquimod was not found to be teratogenic in rat or rabbit teratology studies. In rats at a high maternally toxic dose (28 times human dose on a mg/m2 basis), reduced pup weights and delayed ossification were observed. In developmental studies with offspring of pregnant rats treated with imiquimod (8 times human dose), no adverse effects were demonstrated.
Lactation: It is not known whether topically applied imiquimod is excreted in breast milk.
In controlled clinical trials, the most frequently reported adverse reactions were those of local skin and application site reactions. Some patients also reported systemic reactions. These reactions were usually mild to moderate in intensity; however, severe reactions were reported with 3 times a week application. These reactions were more frequent and more intense with daily application than with 3 times a week application. Overall, in clinical studies applying Aldara 3 times a week, 1.2% (4/327) of the patients discontinued due to local skin/application site reactions.
Reported adverse events in 273 patients treated with Aldara applied 3 times a week are presented at frequencies of: Very common (≥1/10) and common (≥1/100 and <1/10).
Application Site Disorders:
Wart Site Reactions: Very common: Erythema, erosion, excoriation/flaking, oedema, itching, burning. Common: Induration, ulceration, scabbing, vesicle, pain, soreness, burning, irritation, pain, hypopigmentation, itching, rash, sensitivity, soreness, stinging, tenderness.
Remote Site Reactions:
Common: Bleeding, burning, itching, pain, tenderness, tinea cruris.
Body as a Whole:
Common: Influenza symptom, fatigue, fever, fungal infection.
Central and Peripheral Nervous System:
Store below 25°C. Avoid freezing.
D06BB10 - imiquimod ; Belongs to the class of topical antivirals used in the treatment of dermatological diseases.
Cream 5% (single-use, white to off-white) x 12's.