Imiquimod Information
Imiquimod () Indications And Usage
The safety and efficacy of Imiquimod () cream in immunosuppressed patients have not been established. Imiquimod () Cream should be used with caution in patients with pre-existing autoimmune conditions.
The efficacy and safety of Imiquimod () cream have not been established for patients with Basal Cell Nevus Syndrome or Xeroderma Pigmentosum.
Imiquimod () Dosage And Administration
The application frequency for Imiquimod () Cream is different for each indication.
Imiquimod () Dosage Forms And Strengths
Imiquimod () Cream 5%, is supplied in single-use packets each of which contains 250 mg of the cream, equivalent to 12.5 mg of Imiquimod () . Imiquimod () Cream is supplied in a box of 24 packets.
Imiquimod () Contraindications
Imiquimod () Warnings And Precautions
Intense local inflammatory reactions including skin weeping or erosion can occur after few applications of Imiquimod () cream and may require an interruption of dosing. . Imiquimod () cream has the potential to exacerbate inflammatory conditions of the skin, including chronic graft versus host disease.
Administration of Imiquimod () cream is not recommended until the skin is completely healed from any previous drug or surgical treatment.
Exposure to sunlight (including sunlamps) should be avoided or minimized during use of Imiquimod () cream because of concern for heightened sunburn susceptibility. Patients should be warned to use protective clothing (e.g., a 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 their occupation, and those patients with inherent sensitivity to sunlight should exercise caution when using Imiquimod () cream.
Imiquimod () cream shortened the time to skin tumor formation in an animal photoco-carcinogenicity study . The enhancement of ultraviolet carcinogenicity is not necessarily dependent on phototoxic mechanisms. Therefore, patients should minimize or avoid natural or artificial sunlight exposure.
Safety and efficacy have not been established for Imiquimod () cream in the treatment of actinic keratosis with repeated use, i.e. more than one treatment course, in the same area.
The safety of Imiquimod () cream applied to areas of skin greater than 25 cm (e.g. 5 cm X 5 cm) for the treatment of actinic keratosis has not been established
Imiquimod () Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described in reflect exposure to Imiquimod () cream or vehicle in 436 subjects enrolled in two double-blind, vehicle-controlled studies. Subjects applied Imiquimod () cream or vehicle to a 25 cm contiguous treatment area on the face or scalp 2 times per week for 16 weeks.
Local skin reactions were collected independently of the adverse reaction "application site reaction" in an effort to provide a better picture of the specific types of local reactions that might be seen. The most frequently reported local skin reactions were erythema, flaking/scaling/ dryness, and scabbing/crusting. The prevalence and severity of local skin reactions that occurred during controlled studies are shown in the following table.
The adverse reactions that most frequently resulted in clinical intervention (e.g., rest periods, withdrawal from study) were local skin and application site reactions. Overall, in the clinical studies, 2% (5/215) of subjects discontinued for local skin/application site reactions. Of the 215 subjects treated, 35 subjects (16%) on Imiquimod () cream and 3 of 220 subjects (1%) on vehicle cream had at least one rest period. Of these Imiquimod () cream subjects, 32 (91%) resumed therapy after a rest period.
In the AK studies, 22 of 678 (3.2%) of Imiquimod () cream-treated subjects developed treatment site infections that required a rest period off Imiquimod () cream and were treated with antibiotics (19 with oral and 3 with topical). Of the 206 Imiquimod () cream subjects with both baseline and 8-week post-treatment scarring assessments, 6 (2.9%) had a greater degree of scarring scores at 8-weeks post-treatment than at baseline.
In controlled clinical trials for genital warts, the most frequently reported adverse reactions were local skin and application site reactions. Some subjects also reported systemic reactions. Overall, 1.2% (4/327) of the subjects discontinued due to local skin/application site reactions. The incidence and severity of local skin reactions during controlled clinical trials are shown in the following table.
Remote site skin reactions were also reported. The severe remote site skin reactions reported for females were erythema (3%), ulceration (2%), and edema (1%); and for males, erosion (2%), and erythema, edema, induration, and excoriation/flaking (each 1%).
Selected adverse reactions judged to be probably or possibly related to Imiquimod () cream are listed below.
Adverse reactions judged to be possibly or probably related to Imiquimod () cream and reported by more than 1% of subjects included:
The following adverse reactions have been identified during post-approval use of Imiquimod () cream.
Because these reactions are reported voluntarily from a population of uncertain size,it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Imiquimod () Use In Specific Populations
Note:The Maximum Recommended Human Dose (MRHD) was set at 2 packets per treatment of Imiquimod () cream (25 mg Imiquimod () ) for the animal multiple of human exposure ratios presented in this label. If higher doses than 2 packets of Imiquimod () cream are used clinically, then the animal multiple of human exposure would be reduced for that dose. A non-proportional increase in systemic exposure with increased dose of Imiquimod () cream was noted in the clinical pharmacokinetic study conducted in actinic keratosis subjects The AUC after topical application of 6 packets of Imiquimod () cream was 8 fold greater than the AUC after topical application of 2 packets of Imiquimod () cream in actinic keratosis subjects. Therefore, if a dose of 6 packets per treatment of Imiquimod () cream was topically administered to an individual, then the animal multiple of human exposure would be either 1/3 of the value provided in the label (based on body surface area comparisons) or 1/8 of the value provided in the label (based on AUC comparisons). The animal multiples of human exposure calculations were based on weekly dose comparisons for the carcinogenicity studies described in this label. The animal multiples of human exposure calculations were based on daily dose comparisons for the reproductive toxicology studies described in this label.
Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 1, 5 and 20 mg/kg/day Imiquimod () were administered during the period of organogenesis (gestational days 6 – 15) to pregnant female rats. In the presence of maternal toxicity, fetal effects noted at 20 mg/kg/day (577X MRHD based on AUC comparisons) included increased resorptions, decreased fetal body weights, delays in skeletal ossification, bent limb bones, and two fetuses in one litter (2 of 1567 fetuses) demonstrated exencephaly, protruding tongues and low-set ears. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 5 mg/kg/day (98X MRHD based on AUC comparisons).
Intravenous doses of 0.5, 1 and 2 mg/kg/day Imiquimod () were administered during the period of organo-genesis (gestational days 6 – 18) to pregnant female rabbits. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 2 mg/kg/day (1.5X MRHD based on BSA comparisons), the highest dose evaluated in this study, or 1 mg/kg/day (407X MRHD based on AUC comparisons).
A combined fertility and peri- and post-natal development study was conducted in rats. Oral doses of 1, 1.5, 3 and 6 mg/kg/day Imiquimod () were administered to male rats from 70 days prior to mating through the mating period and to female rats from 14 days prior to mating through parturition and lactation. No effects on growth, fertility, reproduction or post-natal development were noted at doses up to 6 mg/kg/day (87X MRHD based on AUC comparisons), the highest dose evaluated in this study. In the absence of maternal toxicity, bent limb bones were noted in the F1 fetuses at a dose of 6 mg/kg/day (87X MRHD based on AUC comparisons). This fetal effect was also noted in the oral rat embryofetal development study conducted with Imiquimod () . No treatment related effects on teratogenicity were noted at 3 mg/kg/day (41X MRHD based on AUC comparisons).
There are no adequate and well-controlled studies in pregnant women. Imiquimod () Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
AK is not a condition generally seen within the pediatric population. The safety and efficacy of Imiquimod () cream for AK in patients less than 18 years of age has not been established.
Safety and efficacy in patients with external genital/perianal warts below the age of 12 years have not been established.
Imiquimod () cream was evaluated in two randomized, vehicle-controlled, double-blind trials involving 702 pediatric subjects with molluscum contagiosum (MC) (470 exposed to Imiquimod () ; median age 5 years, range 2-12 years). Subjects applied Imiquimod () cream or vehicle 3 times weekly for up to 16 weeks. Complete clearance (no MC lesions) was assessed at Week 18. In Study 1, the complete clearance rate was 24% (52/217) in the Imiquimod () cream group compared with 26% (28/106) in the vehicle group. In Study 2,the clearance rates were 24% (60/253) in the Imiquimod () cream group compared with 28% (35/126) in the vehicle group. These studies failed to demonstrate efficacy.
Similar to the studies conducted in adults, the most frequently reported adverse reaction from 2 studies in children with molluscum contagiosum was application site reaction. Adverse events which occurred more frequently in Imiquimod () -treated subjects compared with vehicle-treated subjects generally resembled those seen in studies in indications approved for adults and also included otitis media (5% Imiquimod () vs. 3% vehicle) and conjunctivitis (3% Imiquimod () vs. 2% vehicle).
Erythema was the most frequently reported local skin reaction. Severe local skin reactions reported by Imiquimod () -treated subjects in the pediatric studies included erythema (28%), edema (8%), scabbing/crusting (5%), flaking/scaling (5%), erosion (2%) and weeping/exudate (2%).
Systemic absorption of Imiquimod () across the affected skin of 22 subjects aged 2 to 12 years with extensive MC involving at least 10% of the total body surface area was observed after single and multiple doses at a dosing frequency of 3 applications per week for 4 weeks. The investigator determined the dose applied, either 1, 2 or 3 packets per dose, based on the size of the treatment area and the subject's weight. The overall median peak serum drug concentrations at the end of week 4 was between 0.26 and 1.06 ng/mL except in a 2-year old female who was administered 2 packets of study drug per dose, had a Cmax of 9.66 ng/mL after multiple dosing. Children aged 2-5 years received doses of 12.5 mg (one packet) or 25 mg (two packets) of Imiquimod () and had median multiple-dose peak serum drug levels of approximately 0.2 or 0.5 ng/mL, respectively.
Children aged 6-12 years received doses of 12.5 mg, 25 mg, or 37.5 mg (three packets) and had median multiple dose serum drug levels of approximately 0.1, 0.15, or 0.3 ng/mL, respectively. Among the 20 subjects with evaluable laboratory assessments, the median WBC count decreased by 1.4*10/L and the median absolute neutrophil count decreased by 1.42*10/L.
Imiquimod () Overdosage
The most clinically serious adverse event reported following multiple oral Imiquimod () doses of >200 mg (equivalent to Imiquimod () content of >16 packets) was hypotension, which resolved following oral or intravenous fluid administration.
Imiquimod () Description
Imiquimod () Cream 5% is an immune response modifier for topical administration. Each gram contains 50 mg of Imiquimod () in an off-white oil-in-water vanishing cream base consisting of purified water, oleic acid, white petrolatum, polysorbate 60, glycerin, stearyl alcohol, benzyl alcohol, cetyl alcohol, sorbitan monostearate, xanthan gum, methylparaben, propylparaben.
Chemically, Imiquimod () is 1-(2-methylpropyl)-1-imidazo[4,5-c]quinolin-4-amine. Imiquimod () has a molecular formula of CHN and a molecular weight of 240.3. Its structural formula is:
Imiquimod () Clinical Pharmacology
Systemic absorption of Imiquimod () across the affected skin of 58 subjects with AK was observed with a dosing frequency of 3 applications per week for 16 weeks. Mean peak serum drug concentrations at the end of week 16 were approximately 0.1, 0.2, and 3.5 ng/mL for the applications to face (12.5 mg Imiquimod () , 1 single-use packet), scalp (25 mg, 2 packets) and hands/arms (75 mg, 6 packets), respectively.
The application surface area was not controlled when more than one packet was used. Dose proportionality was not observed. However it appears that systemic exposure may be more dependent on surface area of application than amount of applied dose. The apparent half-life was approximately 10 times greater with topical dosing than the 2 hour apparent half-life seen following subcutaneous dosing, suggesting prolonged retention of drug in the skin. Mean urinary recoveries of Imiquimod () and metabolites combined were 0.08 and 0.15% of the applied dose in the group using 75 mg (6 packets) for males and females, respectively following 3 applications per week for 16 weeks.
Systemic absorption of Imiquimod () was observed across the affected skin of 12 subjects with genital/perianal warts, with an average dose of 4.6 mg. Mean peak drug concentration of approximately 0.4 ng/mL was seen during the study. Mean urinary recoveries of Imiquimod () and metabolites combined over the whole course of treatment, expressed as percent of the estimated applied dose, were 0.11 and 2.41% in the males and females, respectively.
Imiquimod () Clinical Studies
In two double-blind, vehicle-controlled clinical studies, 436 subjects with AK were randomized to treatment with either Imiquimod () cream or vehicle cream 2 times per week for 16 weeks. The studies enrolled subjects with 4 to 8 clinically typical, visible, discrete, nonhyperkeratotic, nonhypertrophic AK lesions within a 25 cm contiguous treatment area on either the face or scalp. The 25 cm contiguous treatment area could be of any dimensions e.g., 5 cm x 5 cm, 3 cm by 8.3 cm, 2 cm by 12.5 cm. Study subjects ranged from 37 to 88 years of age (median 66 years) and 55% had Fitzpatrick skin type I or II. All Imiquimod () -treated subjects were Caucasians.
On a scheduled dosing day, the study cream was applied to the entire treatment area prior to normal sleeping hours and left on for approximately 8 hours. Twice weekly dosing was continued for a total of 16 weeks. The clinical response of each subject was evaluated 8 weeks after the last scheduled application of study cream. Efficacy was assessed by the complete clearance rate, defined as the proportion of subjects at the 8-week post-treatment visit with no (zero) clinically visible AK lesions in the treatment area. Complete clearance included clearance of all baseline lesions, as well as any new or sub-clinical AK lesions which appeared during therapy.
Complete and partial clearance rates are shown in the table below. The partial clearance rate was defined as the percentage of subjects in whom 75% or more baseline AK lesions were cleared.
Sub-clinical AK lesions may become apparent in the treatment area during treatment with Imiquimod () cream. During the course of treatment, 48% (103/215) of subjects experienced an increase in AK lesions relative to the number present at baseline within the treatment area. Subjects with an increase in AK lesions had a similar response to those with no increase in AK lesions.
In a double-blind, placebo-controlled clinical study, 209 otherwise healthy subjects 18 years of age and older with genital/perianal warts were treated with Imiquimod () cream or vehicle control 3 times per week for a maximum of 16 weeks. The median baseline wart area was 69 mm (range 8 to 5525 mm). Subject accountability is shown in the figure below.
Figure 1: Subject Accountability (External Genital Warts)
Data on complete clearance are listed in the table below. The median time to complete wart clearance was 10 weeks.
Imiquimod () How Supplied/storage And Handling
Imiquimod () cream, 5%, is supplied in single-use packets which contain 250 mg of the cream.
Available as: box of 24 packets NDC 0168-0432-24.
Store at 4° - 25°C (39° - 77°F) Avoid freezing.
Imiquimod () Patient Counseling Information
See FDA-Approved Patient Labeling ()
Imiquimod () Cream should be used as directed by a physician. Imiquimod () Cream is for external use only. Contact with the eyes, lips and nostrils should be avoided. The treatment area should not be bandaged or otherwise occluded. Partially-used packets should be discarded and not reused. The prescriber should demonstrate the proper application technique to maximize the benefit of Imiquimod () Cream therapy.
It is recommended that patients wash their hands before and after applying Imiquimod () cream.
Patients may experience local skin reactions during treatment with Imiquimod () Cream (even with normal dosing). Potential local skin reactions include erythema, edema, vesicles, erosions/ulcerations, weeping/exudate, flaking/scaling/dryness, and scabbing/crusting. These reactions can range from mild to severe in intensity and may extend beyond the application site onto the surrounding skin. Patients may also experience application site reactions such as itching and/or burning.
Local skin reactions may be of such an intensity that patients may require rest periods from treatment. Treatment with Imiquimod () Cream can be resumed after the skin reaction has subsided, as determined by the physician. Patients should contact their physician promptly if they experience any sign or symptom at the application site that restricts or prohibits their daily activity or makes continued application of the cream difficult.
Because of local skin reactions, during treatment and until healed, the treatment area is likely to appear noticeably different from normal skin. Localized hypopigmentation and hyperpigmentation have been reported following use of Imiquimod () cream. These skin color changes may be permanent in some patients.
Dosing is 2 times per week for a full 16 weeks, unless otherwise directed by the physician.
However, the treatment period should not be extended beyond 16 weeks due to missed doses or rest periods.
It is recommended that the treatment area be washed with mild soap and water 8 hours following Imiquimod () Cream application.
Most patients using Imiquimod () cream for the treatment of AK experience erythema, flaking/scaling/dryness and scabbing/crusting at the application site with normal dosing.
Use of sunscreen is encouraged, and patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using Imiquimod () Cream.
Sub-clinical AK lesions may become apparent in the treatment area during treatment and may subsequently resolve.
Dosing is 3 times per week to external genital/perianal warts. Imiquimod () Cream treatment should continue until there is total clearance of the genital/perianal warts or for a maximum of 16 weeks.
It is recommended that the treatment area be washed with mild soap and water 6-10 hours following Imiquimod () Cream application.
It is common for patients to experience local skin reactions such as erythema, erosion, excoriation/flaking, and edema at the site of application or surrounding areas. Most skin reactions are mild to moderate.
Sexual (genital, anal, oral) contact should be avoided while Imiquimod () Cream is on the skin.
Application of Imiquimod () Cream in the vagina is considered internal and should be avoided. Female patients should take special care if applying the cream 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 retract the foreskin and clean the area daily. New warts may develop during therapy, as Imiquimod () Cream is not a cure.
The effect of Imiquimod () Cream on the transmission of genital/perianal warts is unknown.
Imiquimod () Cream may weaken condoms and vaginal diaphragms, therefore concurrent use is not recommended.
Should severe local skin reaction occur, the cream should be removed by washing the treatment area with mild soap and water.
E. FOUGERA & CO. A division of Nycomed US Inc. IF2432B Melville, New York 11747 R06/10
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