Aldara

Aldara information, interactions and side effects, Aldara (imiquimod 5%) Cream 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 isostearic acid, cetyl alcohol, stearyl alcohol, white petrolatum, polysorbate 60, sorbitan monostearate, glycerin, xanthan gum, purified water, benzyl alcohol, methylparaben, and propylparaben.

Chemically, imiquimod is 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine. Imiquimod has a molecular formula of C14H16N4 and a molecular weight of 240.3. Its structural formula is:

aldara

INDICATIONS

Actinic Keratosis

Aldara (imiquimod) Cream is indicated for the topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on the face or scalp in immunocompetent adults.

Superficial Basal Cell Carcinoma

Aldara (imiquimod) Cream is indicated for the topical treatment of biopsy-confirmed, primary superficial basal cell carcinoma (sBCC) in immunocompetent adults, with a maximum tumor diameter of 2.0 cm, located on the trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet), only when surgical methods are medically less appropriate and patient follow-up can be reasonably assured.

The histological diagnosis of superficial basal cell carcinoma should be established prior to treatment, since safety and efficacy of Aldara (imiquimod) Cream have not been established for other types of basal cell carcinomas, including nodular and morpheaform (fibrosing or sclerosing) types.

External Genital Warts

Aldara (imiquimod) Cream is indicated for the treatment of external genital and perianal warts/condyloma acuminata in patients 12 years old or older.

Limitations of Use

Aldara (imiquimod) Cream has been evaluated in children ages 2 to 12 years with molluscum contagiosum and these studies failed to demonstrate efficacy [see Use in Specific Populations].

Unevaluated Populations

The safety and efficacy of Aldara (imiquimod) Cream in immunosuppressed patients have not been established.

Aldara (imiquimod) Cream should be used with caution in patients with pre-existing autoimmune conditions.

The efficacy and safety of Aldara (imiquimod) Cream have not been established for patients with Basal Cell Nevus Syndrome or Xeroderma Pigmentosum.

DOSAGE AND ADMINISTRATION

The application frequency for Aldara (imiquimod) Cream is different for each indication.

Aldara (imiquimod) is not for oral, ophthalmic, or intravaginal use.

Actinic Keratosis

Aldara (imiquimod) Cream should be applied 2 times per week for a full 16 weeks to a defined treatment area on the face or scalp (but not both concurrently). The treatment area is defined as one contiguous area of approximately 25 cm² (e.g., 5 cm x 5 cm) on the face (e.g. forehead or one cheek) or on the scalp. Examples of 2 times per week application schedules are Monday and Thursday, or Tuesday and Friday. Aldara (imiquimod) Cream should be applied to the entire treatment area and rubbed in until the cream is no longer visible. No more than one packet of Aldara (imiquimod) Cream should be applied to the contiguous treatment area at each application. Aldara (imiquimod) Cream should be applied prior to normal sleeping hours and left on the skin for approximately 8 hours, after which time the cream should be removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of Aldara (imiquimod) Cream therapy.

It is recommended that patients wash their hands before and after applying Aldara (imiquimod) Cream. Before applying the cream, the patient should wash the treatment area with mild soap and water and allow the area to dry thoroughly (at least 10 minutes).

Contact with the eyes, lips and nostrils should be avoided.

Local skin reactions in the treatment area 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. However, the treatment period should not be extended beyond 16 weeks due to missed doses or rest periods. Response to treatment cannot be adequately assessed until resolution of local skin reactions. Lesions that do not respond to treatment should be carefully reevaluated and management reconsidered.

Aldara (imiquimod) Cream is packaged in single-use packets, with 24 packets supplied per box. Patients should be prescribed no more than 36 packets for the 16-week treatment period. Unused packets should be discarded. Partially-used packets should be discarded and not reused.

Superficial Basal Cell Carcinoma

Aldara (imiquimod) Cream should be applied 5 times per week for a full 6 weeks to a biopsy-confirmed superficial basal cell carcinoma. An example of a 5 times per week application schedule is to apply Aldara (imiquimod) Cream, once per day, Monday through Friday. Aldara (imiquimod) Cream should be applied prior to normal sleeping hours and left on the skin for approximately 8 hours, after which time the cream should be removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of Aldara (imiquimod) Cream therapy.

It is recommended that patients wash their hands before and after applying Aldara (imiquimod) Cream. The patient should wash the treatment area with mild soap and water before applying the cream, and allow the area to dry thoroughly.

The target tumor should have a maximum diameter of 2 cm and be located on the trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet). The treatment area should include a 1 cm margin of skin around the tumor. Sufficient cream should be applied to cover the treatment area, including 1 centimeter of skin surrounding the tumor. Aldara (imiquimod) Cream should be rubbed into the treatment area until the cream is no longer visible.

Table 1. Amount of Aldara (imiquimod) Cream to Use for sBCC

 

Target Tumor Diameter Size of Cream Droplet to be Used (diameter) Approximate Amount of Aldara to be Used
0.5 to < 1.0 cm 4 mm 10 mg
≥ 1.0 to < 1.5 cm 5 mm 25 mg
≥ 1.5 to 2.0 cm 7 mm 40 mg

Contact with the eyes, lips and nostrils should be avoided.

Local skin reactions in the treatment area 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.

Early clinical clearance cannot be adequately assessed until resolution of local skin reactions (e.g. 12 weeks post-treatment). Local skin reactions or other findings (e.g. infection) may require that a patient be seen sooner than the post-treatment assessment for clinical clearance. If there is clinical evidence of persistent tumor at the post-treatment assessment for clinical clearance, a biopsy or other alternative intervention should be considered. Lesions that do not respond to therapy should be carefully re-evaluated and management reconsidered; the safety and efficacy of a repeat course of Aldara (imiquimod) Cream treatment have not been established. If any suspicious lesion arises in the treatment area at any time after a determination of clinical clearance, the patient should seek a medical evaluation.

Aldara (imiquimod) Cream is packaged in single-use packets, with 24 packets supplied per box. Patients should be prescribed no more than 36 packets for the 6-week treatment period. Unused packets should be discarded. Partially-used packets should be discarded and not reused.

External Genital Warts

Aldara (imiquimod) Cream should be applied 3 times per week to external genital/perianal warts. Aldara (imiquimod) Cream treatment should continue until there is total clearance of the genital/perianal warts or for a maximum of 16 weeks. Examples of 3 times per week application schedules are: Monday, Wednesday, Friday or Tuesday, Thursday, Saturday. Aldara (imiquimod) Cream should be applied prior to normal sleeping hours and left on the skin for 6 -10 hours, after which time the cream should be removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of Aldara (imiquimod) Cream therapy.

It is recommended that patients wash their hands before and after applying Aldara (imiquimod) Cream.

A thin layer of Aldara (imiquimod) Cream should be applied to the wart area and rubbed in until the cream is no longer visible. The application site should not be occluded. Following the treatment period the cream should be removed by washing the treated area with mild soap and water.

Local skin reactions 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.

Aldara (imiquimod) Cream 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.

HOW SUPPLIED

Dosage Forms And Strengths

Aldara (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. Aldara (imiquimod) Cream is supplied in a box of 24 packets each.

Storage And Handling

Aldara (imiquimod) Cream, 5%, is supplied in single-use packets which contain 250 mg of the cream. Available as: box of 24 packets NDC 29336-610-24. Store at 4 – 25°C (39 – 77°F).

Avoid freezing.

Keep out of reach of children.

SIDE EFFECTS

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.

Clinical Trials Experience: Actinic Keratosis

The data described below reflect exposure to Aldara (imiquimod) Cream or vehicle in 436 subjects enrolled in two double-blind, vehicle-controlled studies. Subjects applied Aldara (imiquimod) Cream or vehicle to a 25 cm² contiguous treatment area on the face or scalp 2 times per week for 16 weeks.

Table 2: Selected Adverse Reactions Occurring in > 1% of Aldara (imiquimod) -Treated Subjects and at a Greater Frequency than with Vehicle in the Combined Studies (Actinic Keratosis)

 

Preferred Term Aldara Cream
(n= 215)
Vehicle
(n= 221)
Application Site Reaction 71 (33%) 32 (14%)
Upper Resp Tract Infection 33 (15%) 27 (12%)
Sinusitis 16 (7%) 14 (6%)
Headache 11 (5%) 7 (3%)
Carcinoma Squamous 8 (4%) 5 (2%)
Diarrhea 6 (3%) 2 (1%)
Eczema 4 (2%) 3 (1%)
Back Pain 3 (1%) 2 (1%)
Fatigue 3 (1%) 2 (1%)
Fibrillation Atrial 3 (1%) 2 (1%)
Infection Viral 3 (1%) 2 (1%)
Dizziness 3 (1%) 1 ( < 1%)
Vomiting 3 (1%) 1 ( < 1%)
Urinary Tract Infection 3 (1%) 1 ( < 1%)
Fever 3 (1%) 0 (0%)
Rigors 3 (1%) 0 (0%)
Alopecia 3 (1%) 0 (0%)

 

Table 3: Application Site Reactions Reported by > 1% of Aldara (imiquimod) -Treated Subjects and at a Greater Frequency than with Vehicle in the Combined Studies (Actinic Keratosis)

 

Included Term Aldara Cream
n=215
Vehicle
n=221
Itching 44 (20%) 17 (8%)
Burning 13 (6%) 4 (2%)
Bleeding 7 (3%) 1 ( < 1%)
Stinging 6 (3%) 2 (1%)
Pain 6 (3%) 2 (1%)
Induration 5 (2%) 3 (1%)
Tenderness 4 (2%) 3 (1%)
Irritation 4 (2%) 0 (0%)

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.

Table 4: Local Skin Reactions in the Treatment Area as Assessed by the Investigator (Actinic Keratosis)

 

Aldara Cream
(n=215)
Vehicle
(n=220)
All Grades* Severe All Grades* Severe
Erythema 209 (97%) 38 (18%) 206 (93%) 5 (2%)
Flaking/Scaling/Dryness 199 (93%) 16 (7%) 199 (91%) 7 (3%)
Scabbing/Crusting 169 (79%) 18 (8%) 92 (42%) 4 (2%)
Edema 106 (49%) 0 (0%) 22 (10%) 0 (0%)
Erosion/Ulceration 103 (48%) 5 (2%) 20 (9%) 0 (0%)
Weeping/Exudate 45 (22%) 0 (0%) 3 (1%) 0 (0%)
Vesicles 19 (9%) 0 (0%) 2 (1%) 0 (0%)
*Mild, Moderate, or Severe

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 Aldara (imiquimod) Cream and 3 of 220 subjects (1%) on vehicle cream had at least one rest period. Of these Aldara (imiquimod) Cream subjects, 32 (91%) resumed therapy after a rest period.

In the AK studies, 22 of 678 (3.2%) of Aldara (imiquimod) -treated subjects developed treatment site infections that required a rest period off Aldara (imiquimod) Cream and were treated with antibiotics (19 with oral and 3 with topical).

Of the 206 Aldara (imiquimod) 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.

Clinical Trials Experience: Superficial Basal Cell Carcinoma

The data described below reflect exposure to Aldara (imiquimod) Cream or vehicle in 364 subjects enrolled in two double-blind, vehicle-controlled studies. Subjects applied Aldara (imiquimod) Cream or vehicle 5 times per week for 6 weeks. The incidence of adverse reactions reported by > 1% of subjects during the studies is summarized below.

Table 5: Selected Adverse Reactions Reported by > 1% of Aldara (imiquimod) -Treated Subjects and at a Greater Frequency than with Vehicle in the Combined Studies (Superficial Basal Cell Carcinoma)

 

Preferred Term Aldara (imiquimod) Cream
(n= 185)
N %
Vehicle
(n= 179)
N %
Application Site Reaction 52 (28%) 5 (3%)
Headache 14 (8%) 4 (2%)
Back Pain 7 (4%) 1 ( < 1%)
Upper Resp Tract Infection 6 (3%) 2 (1%)
Rhinitis 5 (3%) 1 ( < 1%)
Lymphadenopathy 5 (3%) 1 ( < 1%)
Fatigue 4 (2%) 2 (1%)
Sinusitis 4 (2%) 1 ( < 1%)
Dyspepsia 3 (2%) 2 (1%)
Coughing 3 (2%) 1 ( < 1%)
Fever 3 (2%) 0 (0%)
Dizziness 2 (1%) 1 ( < 1%)
Anxiety 2 (1%) 1 ( < 1%)
Pharyngitis 2 (1%) 1 ( < 1%)
Chest Pain 2 (1%) 0 (0%)
Nausea 2 (1%) 0 (0%)

The most frequently reported adverse reactions were local skin and application site reactions including erythema, edema, induration, erosion, flaking/scaling, scabbing/crusting, itching and burning at the application site. The incidence of application site reactions reported by > 1% of the subjects during the 6 week treatment period is summarized in the table below.

Table 6: Application Site Reactions Reported by > 1% of Aldara (imiquimod) -Treated Subjects and at a Greater Frequency than with Vehicle in the Combined Studies (Superficial Basal Cell Carcinoma)

 

Included Term Aldara Cream
n=185
Vehicle
n=179
Itching 30 (16%) 1 (1%)
Burning 11 (6%) 2 (1%)
Pain 6 (3%) 0 (0%)
Bleeding 4 (2%) 0 (0%)
Erythema 3 (2%) 0 (0%)
Papule(s) 3 (2%) 0 (0%)
Tenderness 2 (1%) 0 (0%)
Infection 2 (1%) 0 (0%)

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 prevalence and severity of local skin reactions that occurred during controlled studies are shown in the following table.

Table 7: Local Skin Reactions in the Treatment Area as Assessed by the Investigator (Superficial Basal Cell Carcinoma)

 

Aldara Cream
n=184
Vehicle
n=178
All Grades* Severe All Grades* Severe
Erythema 184 (100%) 57 (31%) 173 (97%) 4 (2%)
Flaking/Scaling 167 (91%) 7 (4%) 135 (76%) 0 (0%)
Induration 154 (84%) 11 (6%) 94 (53%) 0 (0%)
Scabbing/Crusting 152 (83%) 35 (19%) 61 (34%) 0 (0%)
Edema 143 (78%) 13 (7%) 64 (36%) 0 (0%)
Erosion 122 (66%) 23 (13%) 25 (14%) 0 (0%)
Ulceration 73 (40%) 11 (6%) 6 (3%) 0 (0%)
Vesicles 57 (31%) 3 (2%) 4 (2%) 0 (0%)
*Mild, Moderate, or Severe

The adverse reactions that most frequently resulted in clinical intervention (e.g., rest periods, withdrawal from study) were local skin and application site reactions; 10% (19/185) of subjects received rest periods. The average number of doses not received per subject due to rest periods was 7 doses with a range of 2 to 22 doses; 79% of subjects (15/19) resumed therapy after a rest period. Overall, in the clinical studies, 2% (4/185) of subjects discontinued for local skin/application site reactions.

In the sBCC studies, 17 of 1266 (1.3%) Aldara (imiquimod) -treated subjects developed treatment site infections that required a rest period and treatment with antibiotics.

Clinical Trials Experience: External Genital Warts

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.

Table 8: Local Skin Reactions in the Treatment Area as Assessed by the Investigator (External Genital Warts)

 

AldaraCream Vehicle
Females
n=114
Males
n=156
Females
n=99
Males
n=157
All Grades* Severe All Grades* Severe All Grades* Severe All Grades* Severe
Erythema 74(65%) 4(4%) 90(58%) 6(4%) 21(21%) 0(0%) 34(22%) 0(0%)
Erosion 35(31%) 1(1%) 47(30%) 2(1%) 8(8%) 0(0%) 10(6%) 0(0%)
Excoriation/ Flaking 21(18%) 0(0%) 40(26%) 1(1%) 8(8%) 0(0%) 12(8%) 0(0%)
Edema 20 (18%) 1(1%) 19(12%) 0(0%) 5(5%) 0(0%) 1(1%) 0(0%)
Scabbing 4(4%) 0(0%) 20(13%) 0(0%) 0(0%) 0(0%) 4(3%) 0(0%)
Induration 6(5%) 0(0%) 11(7%) 0(0%) 2(2%) 0(0%) 3(2%) 0(0%)
Ulceration 9(8%) 3(3%) 7(4%) 0(0%) 1(1%) 0(0%) 1(1%) 0(0%)
Vesicles 3(3%) 0(0%) 3(2%) 0(0%) 0(0%) 0(0%) 0(0%) 0(0%)
*Mild, Moderate, or Severe

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 Aldara (imiquimod) Cream are listed below.

Table 9: Selected Treatment Related Reactions (External Genital Warts)

 

Females Males
Aldara Cream
n=117
Vehicle
n=103
Aldara Cream
n =156
Vehicle
n=158
Application Site Disorders:
Application Site Reactions
Wart Site:
Itching 38(32%) 21(20%) 34(22%) 16(10%)
Burning 30(26%) 12(12%) 14(9%) 8(5%)
Pain 9(8%) 2(2%) 3(2%) 1(1%)
Soreness 3(3%) 0(0%) 0(0%) 1(1%)
Fungal Infection* 13(11%) 3(3%) 3(2%) 1(1%)
Systemic Reactions:
Headache 5(4%) 3(3%) 8(5%) 3(2%)
Influenza-like symptoms 4(3%) 2(2%) 2(1%) 0(0%)
Myalgia 1(1%) 0(0%) 2(1%) 1(1%)
*Incidences reported without regard to causality with Aldara Cream.

Adverse reactions judged to be possibly or probably related to Aldara (imiquimod) Cream and reported by more than 1% of subjects included:

Application Site Disorders: burning, hypopigmentation, irritation, itching, pain, rash, sensitivity, soreness, stinging, tenderness

Remote Site Reactions: bleeding, burning, itching, pain, tenderness, tinea cruris

Body as a Whole: fatigue, fever, influenza-like symptoms

Central and Peripheral Nervous System Disorders: headache

Gastro-Intestinal System Disorders: diarrhea

Musculo-Skeletal System Disorders: myalgia.

Clinical Trials Experience: Dermal Safety Studies

Provocative repeat insult patch test studies involving induction and challenge phases produced no evidence that Aldara (imiquimod) Cream causes photoallergenicity or contact sensitization in healthy skin; however, cumulative irritancy testing revealed the potential for Aldara (imiquimod) Cream to cause irritation, and application site reactions were reported in the clinical studies.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Aldara (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.

Application Site Disorders: tingling at the application site.

Body as a Whole: angioedema.

Cardiovascular: capillary leak syndrome, cardiac failure, cardiomyopathy, pulmonary edema, arrhythmias (tachycardia, atrial fibrillation, palpitations), chest pain, ischemia, myocardial infarction, syncope.

Endocrine: thyroiditis.

Gastro-Intestinal System Disorders: abdominal pain.

Hematological: decreases in red cell, white cell and platelet counts (including idiopathic thrombocytopenic purpura), lymphoma.

Hepatic: abnormal liver function.

Infections and Infestations: herpes simplex.

Musculo-Skeletal System Disorders: arthralgia.

Neuropsychiatric: agitation, cerebrovascular accident, convulsions (including febrile convulsions), depression, insomnia, multiple sclerosis aggravation, paresis, suicide.

Respiratory: dyspnea.

Urinary System Disorders: proteinuria, dysuria, urinary retention.

Skin and Appendages: exfoliative dermatitis, erythema multiforme, hyperpigmentation, hypertrophic scar.

Vascular: Henoch-Schonlein purpura syndrome.

PRECAUTIONS

Local Inflammatory Reactions

Intense local inflammatory reactions including skin weeping or erosion can occur after few applications of Aldara (imiquimod) Cream and may require an interruption of dosing. Aldara (imiquimod) Cream has the potential to exacerbate inflammatory conditions of the skin, including chronic graft versus host disease.

Severe local inflammatory reactions of the female external genitalia can lead to severe vulvar swelling. Severe vulvar swelling can lead to urinary retention. Dosing should be interrupted or discontinued for severe vulvar swelling.

Administration of Aldara (imiquimod) Cream is not recommended until the skin is completely healed from any previous drug or surgical treatment.

Systemic Reactions

Flu-like signs and symptoms may accompany, or even precede, local inflammatory reactions and may include malaise, fever, nausea, myalgias and rigors. An interruption of dosing should be considered.

Ultraviolet Light Exposure

Exposure to sunlight (including sunlamps) should be avoided or minimized during use of Aldara (imiquimod) Cream because of concern for heightened sunburn susceptibility. Patients should be warned to use protective clothing (e.g., a hat) when using Aldara (imiquimod) Cream. Patients with sunburn should be advised not to use Aldara (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 Aldara (imiquimod) Cream.

Aldara (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.

Unevaluated Uses: Actinic Keratosis

Safety and efficacy have not been established for Aldara (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 Aldara (imiquimod) Cream applied to areas of skin greater than 252 cm (e.g. 5cm X 5cm) for the treatment of actinic keratosis has not been established.

Unevaluated Uses: Superficial Basal Cell Carcinoma

The safety and efficacy of Aldara (imiquimod) Cream have not been established for other types of basal cell carcinomas (BCC), including nodular and morpheaform (fibrosing or sclerosing) types. Aldara (imiquimod) Cream is not recommended for treatment of BCC subtypes other than the superficial variant (i.e., sBCC). Patients with sBCC treated with Aldara (imiquimod) Cream should have regular follow-up of the treatment site.

The safety and efficacy of treating sBCC lesions on the face, head and anogenital area have not been established.

Unevaluated Uses: External Genital Warts

Aldara (imiquimod) Cream has not been evaluated for the treatment of urethral, intra-vaginal, cervical, rectal, or intra-anal human papilloma viral disease.

Patient Counseling Information

See FDA-Approved Patient Labeling

General Information: All Indications

Aldara (imiquimod) Cream should be used as directed by a physician. Aldara (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 Aldara (imiquimod) Cream therapy. It is recommended that patients wash their hands before and after applying Aldara (imiquimod) cream.

Local Skin Reactions: All Indications

Patients may experience local skin reactions during treatment with Aldara (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 intensity that patients may require rest periods from treatment. Treatment with Aldara (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 Aldara (imiquimod) Cream. These skin color changes may be permanent in some patients.

Systemic Reactions: All Indications

Patients may experience flu-like systemic signs and symptoms during treatment with Aldara (imiquimod) Cream (even with normal dosing). Systemic signs and symptoms may include malaise, fever, nausea, myalgias and rigors. An interruption of dosing should be considered.

Patients Being Treated for Actinic Keratosis (AK)

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 Aldara (imiquimod) Cream application.

Most patients using Aldara (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 Aldara (imiquimod) Cream.

Sub-clinical AK lesions may become apparent in the treatment area during treatment and may subsequently resolve.

Patients Being Treated for Superficial Basal Cell Carcinoma (sBCC)

Dosing is 5 times per week for a full 6 weeks, unless otherwise directed by the physician. However, the treatment period should not be extended beyond 6 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 Aldara Cream application.

Most patients using Aldara (imiquimod) Cream for the treatment of sBCC experience erythema, edema, induration, erosion, scabbing/crusting and flaking/scaling 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 Aldara (imiquimod) Cream.

The clinical outcome of therapy can be determined after resolution of application site reactions and/or local skin reactions.

Patients with sBCC treated with Aldara (imiquimod) Cream should have regular follow-up to re-evaluate the treatment site.

Patients Being Treated for External Genital Warts

Dosing is 3 times per week to external genital/perianal warts. Aldara (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 Aldara (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 Aldara (imiquimod) Cream is on the skin.

Application of Aldara (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 severe swelling, and may cause difficulty in passing urine or inability to urinate.

Uncircumcised males treating warts under the foreskin should retract the foreskin and clean the area daily.

New warts may develop during therapy, as Aldara (imiquimod) Cream is not a cure.

The effect of Aldara (imiquimod) Cream on the transmission of genital/perianal warts is unknown.

Aldara (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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In an oral (gavage) rat carcinogenicity study, imiquimod was administered to Wistar rats on a 2X/week (up to 6 mg/kg/day) or daily (3 mg/kg/day) dosing schedule for 24 months. No treatment related tumors were noted in the oral rat carcinogenicity study up to the highest doses tested in this study of 6 mg/kg administered 2X/week in female rats (87X MRHD based on weekly AUC comparisons), 4 mg/kg administered 2X/week in male rats (75X MRHD based on weekly AUC comparisons) or 3 mg/kg administered 7X/week to male and female rats (153X MRHD based on weekly AUC comparisons).

In a dermal mouse carcinogenicity study, imiquimod cream (up to 5 mg/kg/application imiquimod or 0.3% imiquimod cream) was applied to the backs of mice 3X/week for 24 months. A statistically significant increase in the incidence of liver adenomas and carcinomas was noted in high dose male mice compared to control male mice (251X MRHD based on weekly AUC comparisons). An increased number of skin papillomas was observed in vehicle cream control group animals at the treated site only. The quantitative composition of the vehicle cream used in the dermal mouse carcinogenicity study is the same as the vehicle cream used for Aldara Cream, minus the active moiety (imiquimod).

In a 52-week dermal photoco-carcinogenicity study, the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing (3X/week; 40 weeks of treatment followed by 12 weeks of observation) with concurrent exposure to UV radiation (5 days per week) with the Aldara (imiquimod) Cream vehicle alone. No additional effect on tumor development beyond the vehicle effect was noted with the addition of the active ingredient, imiquimod, to the vehicle cream.

Imiquimod revealed no evidence of mutagenic or clastogenic potential based on the results of five in vitro genotoxicity tests (Ames assay, mouse lymphoma L5178Y assay, Chinese hamster ovary cell chromosome aberration assay, human lymphocyte chromosome aberration assay and SHE cell transformation assay) and three in vivo genotoxicity tests (rat and hamster bone marrow cytogenetics assay and a mouse dominant lethal test).

Daily oral administration of imiquimod to rats, throughout mating, gestation, parturition and lactation, demonstrated no effects on growth, fertility or reproduction, at doses up to 87X MRHD based on AUC comparisons.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Note: The Maximum Recommended Human Dose (MRHD) was set at 2 packets per treatment of Aldara Cream (25 mg imiquimod) for the animal multiple of human exposure ratios presented in this label. If higher doses than 2 packets of Aldara (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 Aldara (imiquimod) Cream was noted in the clinical pharmacokinetic study conducted in actinic keratosis subjects. The AUC after topical application of 6 packets of Aldara (imiquimod) Cream was 8 fold greater than the AUC after topical application of 2 packets of Aldara (imiquimod) Cream in actinic keratosis subjects. Therefore, if a dose of 6 packets per treatment of Aldara (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 organogenesis (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. Aldara (imiquimod) Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether imiquimod is excreted in human milk following use of Aldara (imiquimod) Cream. Because many drugs are excreted in human milk, caution should be exercised when Aldara (imiquimod) Cream is administered to nursing women.

Pediatric Use

AK and sBCC are not conditions generally seen within the pediatric population. The safety and efficacy of Aldara (imiquimod) Cream for AK or sBCC in patients less than 18 years of age have not been established.

Safety and efficacy in patients with external genital/perianal warts below the age of 12 years have not been established.

Aldara (imiquimod) Cream was evaluated in two randomized, vehicle-controlled, double-blind trials involving 702 pediatric subjects with molluscum contagiosum (MC) (470 exposed to Aldara (imiquimod) ; median age 5 years, range 2-12 years). Subjects applied Aldara (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 Aldara (imiquimod) Cream group compared with 26% (28/106) in the vehicle group. In Study 2, the clearance rates were 24% (60/253) in the Aldara (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 Aldara (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% Aldara (imiquimod) vs. 3% vehicle) and conjunctivitis (3% Aldara (imiquimod) vs. 2% vehicle).

Erythema was the most frequently reported local skin reaction. Severe local skin reactions reported by Aldara (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 25 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*109/L and the median absolute neutrophil count decreased by 1.42*109/L.

Geriatric Use

Of the 215 subjects treated with Aldara (imiquimod) Cream in the AK clinical studies, 127 subjects (59%) were 65 years and older, while 60 subjects (28%) were 75 years and older. Of the 185 subjects treated with Aldara (imiquimod) Cream in the sBCC clinical studies, 65 subjects (35%) were 65 years and older, while 25 subjects (14%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. No other clinical experience has identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

OVERDOSE

Topical overdosing of Aldara (imiquimod) Cream could result in an increased incidence of severe local skin reactions and may increase the risk for systemic reactions.

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.

530 read