Aldara

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Description for Aldara

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:

Uses for Aldara

Actinic Keratosis

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

Superficial Basal Cell Carcinoma

ALDARA 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.

Establish the histological diagnosis of superficial basal cell carcinoma prior to treatment. The safety and effectiveness of ALDARA have not been established for other types of basal cell carcinomas (BCC), including nodular and morpheaform (fibrosing or sclerosing) types.

External Genital Warts

ALDARA is indicated for the topical treatment of external genital and perianal warts (EGW) in immunocompetent patients 12 years of age and older.

Dosage for Aldara

Important Dosage And Administration Instructions

ALDARA is for topical use only. ALDARA is not for oral, ophthalmic, or intravaginal use. Instruct patients on proper application technique.

Wash hands before and after applying ALDARA. Wash the treatment area with mild soap and water and allow the area to dry thoroughly (at least 10 minutes) before applying ALDARA.

If an ALDARA dose is missed, apply the next dose at the regularly scheduled time.

Avoid contact with the eyes, lips, nostrils, or inside the anus and vagina.

For patients with AK and sBCC, prescribe no more than 3 boxes (36 packets) of ALDARA for the entire treatment period. For EGW, one packet of ALDARA contains sufficient cream to cover a wart area of up to 20 cm².

Discard partially used packets and do not reuse.

Dosage And Administration For Actinic Keratosis

Apply ALDARA topically once daily before bedtime 2 times per week for a full 16 weeks to a defined treatment area of AK on the face or scalp (but not both concurrently). A treatment area is defined as one contiguous area of approximately 25 cm² (e.g., 5 cm × 5 cm) on the face (e.g., forehead or one cheek) or on the scalp. Apply ALDARA to the entire treatment area and rub in until the cream is no longer visible. Apply no more than 1 packet of ALDARA to the contiguous treatment area at each application. Leave ALDARA on the skin for approximately 8 hours and then remove with mild soap and water.

For local skin reactions a dosage interruption of several days may be taken if required by the patient's discomfort or severity of the local skin reaction [see WARNINGS AND PRECAUTIONS]. Do not extend treatment beyond 16 weeks due to missed doses or rest periods. Assess response to treatment after resolution of local skin reactions.

Dosage And Administration For Superficial Basal Cell Carcinoma

Apply ALDARA topically once daily before bedtime 5 times per week for a full 6 weeks to a biopsy-confirmed sBCC. 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 amount of cream needed to cover the target tumor, including 1 cm of skin surrounding the tumor, is presented in Table 1. Rub ALDARA into the treatment area until the cream is no longer visible. Leave ALDARA on the skin for approximately 8 hours and then remove with mild soap and water.

Table 1: Amount of ALDARA 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

For local skin reactions a dosage interruption of several days may be taken if required by the patient's discomfort or severity of the local skin reaction [see WARNINGS AND PRECAUTIONS].

Assess for early clinical clearance after 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, consider a biopsy or other alternative intervention. Instruct patients to contact their healthcare provider if any suspicious lesion arises in the treatment area at any time after a determination of clinical clearance [see Clinical Studies].

Dosage And Administration For External Genital Warts

Apply a thin layer of ALDARA topically once daily before bedtime 3 times per week to EGW until there is total clearance of the genital/perianal warts or for a maximum of 16 weeks. Rub in until the cream is no longer visible. Do not occlude the application site. Leave ALDARA on the skin for 6 to 10 hours and then remove with mild soap and water.

For local skin reactions, a dosage interruption of several days may be taken if required by the patient's discomfort or severity of the local skin reaction [see WARNINGS AND PRECAUTIONS]. Treatment may resume once the reaction subsides. Nonocclusive dressings such as cotton gauze or cotton underwear may be used to manage skin reactions.

Inform uncircumcised patients treating warts under the foreskin to retract the foreskin and clean the area daily.

ALDARA may weaken condoms and vaginal diaphragms; therefore, concurrent use is not recommended.

HOW SUPPLIED

Dosage Forms And Strengths

Cream, 5%: a white to faintly yellow cream in unit-dose packets, with each packet containing 250 mg of cream, equivalent to 12.5 mg of imiquimod.

Storage And Handling

ALDARA (imiquimod) cream, 5% is supplied in unit-dose packets each of which contains 250 mg of a white to faintly yellow cream:

Box of 12 packets, NDC 99207-260-12. Store at 4° to 25°C (39° to 77°F). Avoid freezing.

Distributed by: Bausch Health US, LLC Bridgewater, NJ 08807 USA. Manufactured By: 3M Health Care Limited Loughborough Leicestershire. Revised: Sep 2024

Side Effects for Aldara

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Local Skin Reactions [see WARNINGS AND PRECAUTIONS]
• Local Hypopigmentation Reactions [see WARNINGS AND PRECAUTIONS]
• Systemic Reactions [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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.

Actinic Keratosis

The data described below reflect exposure to ALDARA or vehicle in 436 subjects with AK enrolled in two double-blind, vehicle-controlled trials (Studies AK1 and AK2) [see Clinical Studies]. Subjects applied ALDARA, 5% or vehicle topically, to a 25 cm² contiguous treatment area on the face or scalp once daily 2 times per week for 16 weeks.

The incidence of selected adverse reactions reported by ≥1% of subjects during the trials is presented in Table 2.

Table 2: Selected Adverse Reactions Occurring in ≥1% of ALDARA-Treated Subjects with AK and at a Greater Frequency than Vehicle in Studies AK1 and AK2

	ALDARA (n=215)	Vehicle (n=221)
Application Site Reaction	71 (33%)	32 (14%)
Upper Respiratory 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%)

The incidence of application site reactions reported by >1% of subjects during the trials is presented in Table 3.

Table 3: Application Site Reactions Reported by >1% of ALDARA-Treated Subjects with AK and at a Greater Frequency than Vehicle in Studies AK1 and AK2

	ALDARA (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”. The incidence and severity of local skin reactions that occurred during controlled trials re shown in Table 4.

Table 4: Local Skin Reactions in the Treatment Area of ALDARA-Treated Subjects with AK as Assessed by the Investigator in Studies AK1 and AK2

	ALDARA (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%)
W eeping/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 trial) were local skin and application site reactions. In the trials, 2% (5/215) of subjects discontinued for local skin/application site reactions. Of the 215 subjects treated, 35 subjects (16%) on ALDARA and 3 of 220 subjects (1%) on vehicle had at least one rest period. Of the ALDARA-treated subjects, 32 (91%) resumed therapy after a rest period.

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

Of the 206 ALDARA-treated 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.

Superficial Basal Cell Carcinoma

The data described below reflect exposure to ALDARA or vehicle in 364 subjects with sBCC enrolled in two double-blind, vehicle-controlled trials (sBCC1 and sBCC2) [see Clinical Studies]. Subjects applied ALDARA, 5% or vehicle topically 5 times per week for 6 weeks.

The incidence of selected adverse reactions reported by ≥1% of subjects during the trials is summarized in Table 5.

Table 5: Selected Adverse Reactions Reported by ≥1% of ALDARA-Treated Subjects with sBCC and ata Greater Frequency than Vehicle in Studies sBCC1 and sBCC2

	ALDARA (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 Respiratory 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. The incidence of application site reactions reported by >1% of the subjects during the 6-week treatment period is summarized in Table 6.

Table 6: Application Site Reactions Reported by >1% of ALDARA-Treated Subjects with sBCC and at a Greater Frequency than Vehicle in Studies sBCC1 and sBCC2

	ALDARA (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”. The incidence and severity of local skin reactions that occurred during the controlled trials are shown in Table 7.

Table 7: Local Skin Reactions in the Treatment Area of ALDARA-Treated Subjects with sBCC as Assessed by the Investigator in Studies sBCC1 and sBCC2

	ALDARA (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 trial) were local skin and application site reactions; 10% (19/185) of ALDARA-treated subjects received rest periods. The average number of doses not received per ALDARA-treated 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 trials, 2% (4/185) of ALDARA-treated subjects discontinued for local skin/application site reactions.

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

External Genital Warts

In controlled clinical trials for EGW, including a double-blind, vehicle-controlled clinical trial in 209 adult subjects with EGW (Study EGW1) [see Clinical Studies], ALDARA, 5% was applied topically to EGW in 109 subjects. Selected adverse reactions in ALDARA-treated subjects are listed below (see Table 8).

Table 8: Selected Adverse Reactions in ALDARA-Treated Subjects with EGW in Vehicle-Controlled Clinical Trials

	Females		Males
	ALDARA (n=117)	Vehicle (n=103)	ALDARA (n=156)	Vehicle (n=158)
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%)

The most frequently reported adverse reactions were local skin and application site reactions.

Overall, 1.2% (4/327) of the subjects discontinued treatment due to local skin/application site reactions. The incidence and severity of local skin reactions during controlled clinical trials are shown in Table 9.

Table 9: Local Skin Reactions in the Treatment Area of ALDARA-Treated Subjects with EGW as Assessed by the Investigator in Vehicle-Controlled Clinical Trials

	ALDARA				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%). Other adverse reactions reported by more than 1% of ALDARA-treated subjects included:

Application Site Disorders: hypopigmentation, irritation, rash, sensitivity, stinging, tenderness

Body as a Whole: fatigue, fever

Gastrointestinal System Disorders: diarrheaRemote Site Reactions: bleeding, burning, itching, pain, tenderness, tinea cruris

Postmarketing Experience

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

Gastrointestinal 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

Musculoskeletal 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, hypertrophic scar, hyperpigmentation, hypopigmentation, including complete depigmentation.

Vascular: Henoch-Schönlein purpura syndrome

Drug Interactions for Aldara

No Information provided

Warnings for Aldara

Included as part of the PRECAUTIONS section.

Precautions for Aldara

Local Skin Reactions

Local skin reactions including skin weeping or erosion have been reported with ALDARA and can occur after a few applications [see ADVERSE REACTIONS]. Concomitant use of ALDARA and any other imiquimod products, in the same treatment area, may increase the risk for and severity of local skin reactions.

ALDARA 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 and urinary retention.

Avoid sexual (genital, anal, oral) contact while ALDARA is on the skin.

To reduce the risk of local skin reactions and manage local skin reactions that occur with ADLARA treatment:

• Avoid concomitant use of ALDARA with any other imiquimod product in the same treatment area.
• Avoid application of ALDARA to skin that is not intact (i.e., any area with an abrasion, cut, burn, rash, infection, or other condition that has altered skin integrity).
• An interruption of dosing may be required for local skin reactions [see DOSAGE AND ADMINISTRATION]. Interrupt dosing or discontinue ALDARA for severe vulvar swelling [see DOSAGE AND ADMINISTRATION].
• If severe local skin reactions occur, instruct patients to remove ALDARA by washing the treatment area with mild soap and water.

Local Hypopigmentation Reactions

Cases of hypopigmentation, including complete depigmentation, were reported during postmarketing use of ALDARA. In some cases, hypopigmentation and complete depigmentation did not improve or resolve with treatment and persisted for up to 60 months at the time of reporting. Discontinue ALDARA if hypopigmentation develops.

Systemic Reactions

Flu-like signs and symptoms have been reported with use of ALDARA and may accompany, or even precede, local inflammatory reactions [see ADVERSE REACTIONS]. Signs and symptoms may include malaise, fever, nausea, myalgias, and rigors. Concomitant use of ALDARA and any other imiquimod products may increase the risk for and severity of systemic reactions. Consider an interruption of dosing if systemic reactions occur.

Ultraviolet Light Exposure Risks

ALDARA may cause heightened sunburn susceptibility. Avoid or minimize exposure to sunlight (including sunlamps) during use of ALDARA. Instruct patients to use sunscreen and wear protective clothing (e.g., a hat). Advise patients not to use ALDARA until fully recovered from a sunburn.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Important Administration Instructions

Inform all patients of the following: [see DOSAGE AND ADMINISTRATION]

• ALDARA is for topical use only; avoid contact with the eyes, lips, nostrils, or inside the anus and vagina. Instruct patients to rinse their mouth or eyes with water right away if contact with these areas occur.
• Wash hands before and after applying ALDARA.
• If an ALDARA dose is missed, apply the next dose at the regularly scheduled time.
• Discard and do not reuse partially used packets.

Inform patients with EGW of the following [see DOSAGE AND ADMINISTRATION]:

• Uncircumcised patients treating warts under the foreskin should retract the foreskin and clean the area daily.
• ALDARA may weaken condoms and vaginal diaphragms; therefore, concurrent use is not recommended.
• Avoid sexual (genital, anal, oral) contact while ALDARA is on the skin.
• Do not bandage or otherwise occlude the treatment area.

Lactation

Advise breastfeeding women to avoid application of ALDARA to areas with increased risk for potential ingestion by or ocular exposure to the breastfeeding child  [see Use In Specific Populations].

Local Skin Reactions

Inform patients of the following [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]:

• Local skin reactions may occur during treatment with ALDARA, ranging from mild to severe in intensity and extending beyond the application site onto the surrounding skin, and may require an interruption of dosing.
• For female patients being treated for EGW, apply ALDARA at the opening of the vagina, avoiding intravaginal application because local skin reactions may cause difficulty in passing urine.
• If severe local skin reactions occur, remove ALDARA by washing the treatment area with mild soap and water.
• Contact their healthcare provider promptly if they experience any sign or symptom at the application site that restricts or prohibits their daily activity or makes continued application of ALDARA difficult.
• Because of local skin reactions, during treatment and until healed, the treatment area is likely to appear noticeably different from normal skin.

Local Hypopigmentation Reactions

Inform patients that cases of hypopigmentation, including complete depigmentation, were reported during postmarketing use of ALDARA and, in some cases, hypopigmentation and complete depigmentation did not improve or resolve with treatment and persisted for up to 60 months at the time of reporting. Advise patient to inform their healthcare provider if hypopigmentation is observed [see WARNINGS AND PRECAUTIONS].

Systemic Reactions

Inform patients that they may experience flu-like systemic signs and symptoms during treatment with ALDARA and these symptoms may require an interruption of dosing [see WARNINGS AND PRECAUTIONS].

Ultraviolet Light Exposure Risks

Instruct patients to avoid or minimize exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using ALDARA. Instruct patients to use sunscreen and to wear protective clothing, and to not use ALDARA if sunburned [see WARNINGS AND PRECAUTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In an oral (gavage) rat carcinogenicity study, imiquimod was administered to Wistar rats on a 2 times per 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 2 times per week in female rats (87 times the MRHD based on weekly AUC comparison), 4 mg/kg administered 2 times per week in male rats (75 times the MRHD based on weekly AUC comparison), or 3 mg/kg administered 7 times per week to male and female rats (153 times the MRHD based on weekly AUC comparison).

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 3 times per 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 (251 times the MRHD based on weekly AUC comparison). An increased number of skin papillomas was observed in vehicle cream control group animals at the treated site only.

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 87 times the MRHD based on AUC comparison.

Use In Specific Populations

Pregnancy

Risk Summary

Available data from case reports and case series of use with imiquimod during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are no controlled or large-scale epidemiologic studies and no exposure registries with imiquimod use in pregnant women.

In animal reproduction studies, there were no adverse developmental effects observed after oral administration of imiquimod in pregnant rats and intravenous administration of imiquimod in pregnant rabbits during organogenesis at doses up to 98 times and 407 times, respectively, the maximum recommended human dose (MRHD) (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

The MRHD was set at 2 packets per treatment of ALDARA (25 mg imiquimod) for the animal multiples of human exposure presented 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 to pregnant female rats. In the presence of maternal toxicity, fetal effects noted at 20 mg/kg/day (577 times the MRHD based on AUC comparison) 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 malformation were noted at 5 mg/kg/day (98 times the MRHD based on AUC comparison).

Intravenous doses of 0.5, 1, and 2 mg/kg/day imiquimod were administered during the period of organogenesis to pregnant female rabbits. No treatment-related effects on embryofetal toxicity or malformation were noted at 2 mg/kg/day (1.5 times the MRHD based on BSA comparison), the highest dose evaluated in this study, or 1 mg/kg/day (407 times the MRHD based on AUC comparison).

A combined fertility and peri- and postnatal 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 postnatal development were noted at doses up to 6 mg/kg/day (87 times the MRHD based on AUC comparison), 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 (87 times the MRHD based on AUC comparison). This fetal effect was also noted in the oral rat embryofetal development study conducted with imiquimod. No treatment-related malformations were noted at 3 mg/kg/day (41 times the MRHD based on AUC comparison).

Lactation

Risk Summary

There is no information available on the presence of imiquimod in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production after topical application of ALDARA to women who are breastfeeding. Systemic concentration following topical administration of imiquimod cream is low; therefore, transfer of ALDARA into breastmilk is likely to be low [see CLINICAL PHARMACOLOGY]. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for ALDARA and any potential adverse effects on the breastfed infant from ALDARA or from the underlying maternal condition.

Clinical Considerations

Avoid application of ALDARA to areas with increased risk for potential ingestion by or ocular exposure to the breastfeeding child.

Pediatric Use

Actinic Keratosis And Superficial Basal Cell Carcinoma

The safety and effectiveness of ALDARA for the treatment of AK or sBCC in pediatric patients have not been established.

External Genital Warts

The safety and effectiveness of ALDARA for the treatment of EGW in pediatric patients 12 years of age and older have been established. Use of ALDARA for this indication is supported by evidence from adequate and well controlled trials in adults [see Clinical Studies]. The safety and effectiveness of ALDARA for the treatment of EGW in pediatric patients less than 12 years of age have not been established.

Molluscum Contagiosum

The safety and effectiveness of ALDARA for the treatment of molluscum contagiosum (MC) in pediatric patients have not been established. Safety and effectiveness of ALDARA was not demonstrated in two randomized, vehicle-controlled, double-blind trials involving 702 pediatric subjects with MC (470 exposed to ALDARA; median age 5 years, range 2–12 years).

Adverse reactions reported in pediatric subject with MC (and not previously reported) included otitis media (5% ALDARA vs. 3% vehicle) and conjunctivitis (3% ALDARA vs. 2% vehicle).

In a pharmacokinetics trial in subjects aged 2 to 12 years with extensive MC involving a least 10% of total body surface area; among the 20 subjects with evaluable laboratory assessments, the median white blood cell (WBC) count decreased by 1.4 x 10⁹/L and the median absolute neutrophil count decreased by 1.42 x 10⁹/L.

Geriatric Use

Of the 215 subjects treated with ALDARA in the AK clinical trials, 127 subjects (59%) were 65 years of age or older, while 60 subjects (28%) were 75 years of age or older. Of the 185 subjects treated with ALDARA in the sBCC clinical trials, 65 subjects (35%) were 65 years of age or older, while 25 subjects (14%) were 75 years of age or older. No overall differences in safety or effectiveness of ALDARA have been observed between subjects 65 years of age and older and younger adult subjects.

Overdose Information for Aldara

Topical overdosing of Aldara 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.

Contraindications for Aldara

No Information Provided

Clinical Pharmacology for Aldara

Mechanism Of Action

The mechanism of action of ALDARA in treating AK, sBCC, and EGW lesions is unknown.

Pharmacodynamics

Actinic Keratosis

In a trial of 18 subjects with AK comparing ALDARA to vehicle, increases from baseline in Week 2 biomarker levels were reported for CD3, CD4, CD8, CD11c, and CD68 for ALDARA-treated subjects; however, the clinical relevance of these findings is unknown.

Superficial Basal Cell Carcinoma

An open-label trial in 6 subjects with sBCC suggests that treatment with ALDARA may increase the infiltration of lymphocytes, dendritic cells, and macrophages into the tumor lesion; however, the clinical significance of these findings is unknown.

External Genital

Warts Imiquimod has no direct antiviral activity in cell culture. A trial in 22 subjects with EGW comparing ALDARA and vehicle shows that ALDARA induces mRNA encoding cytokines including interferon-α 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.

Pharmacokinetics

Absorption

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 unit-dose packet), scalp (25 mg, 2 packets), and hands/arms (75 mg, 6 packets), respectively.

Table 10: Mean Serum Imiquimod Concentration in Adults Following Administration of the Last Topical Dose during Week 16 (Actinic Keratosis)

Amount of ALDARA Applied	Mean Peak Serum Imiquimod Concentration [Cmax]
12.5 mg (1 packet)	0.1 ng/mL
25 mg (2 packets)	0.2 ng/mL
75 mg (6 packets)	3.5 ng/mL

The application surface area was not controlled when more than 1 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 trial. 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.

Clinical Studies

Actinic Keratosis

In two double-blind, vehicle-controlled clinical trials, 436 subjects with AK were randomized to treatment with either ALDARA, 5% or vehicle applied topically once daily 2 times per week for 16 weeks (Studies AK1 and AK2). The trials enrolled subjects with 4 to 8 clinically typical, visible, discrete, nonhyperkeratotic, nonhypertrophic AK lesions within a 25 cm² contiguous treatment area on either the face or scalp. The 25 cm² contiguous treatment area could be of any dimensions (e.g., 5 cm × 5 cm, 3 cm × 8.3 cm, 2 cm × 12.5 cm). Trial subjects ranged from 37 to 88 years of age (median 66 years) and 55% had Fitzpatrick skin type I or II. All ALDARA-treated subjects were White.

On a scheduled dosing day, the trial 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 trial 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 subclinical AK lesions which appeared during therapy.

Complete and partial clearance rates are shown in Table 11. The partial clearance rate was defined as the percentage of subjects in whom 75% or more baseline AK lesions were cleared.

Table 11: Clearance Rates of AK at 8 Weeks Post-Treatment

Complete Clearance Rates (100% AK Lesions Cleared)
Trial	ALDARA	Vehicle
Study AK1	46% (49/107)	3% (3/110)
Study AK2	44% (48/108)	4% (4/111)
Partial and Complete Clearance Rates (75% or More Baseline AK Lesions Cleared)
Trial	ALDARA	Vehicle
Study AK1	60% (64/107)	10% (11/110)
Study AK2	58% (63/108)	14% (15/111)

During treatment, 48% (103/215) of ALDARA-treated 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.

Superficial Basal Cell Carcinoma

In two double-blind, vehicle-controlled clinical trials, 364 subjects with primary sBCC were treated with ALDARA, 5% or vehicle applied topically once daily 5 times per week for 6 weeks (Studies sBCC1 and sBCC2). Target tumors were biopsy-confirmed sBCC and had a minimum area of 0.5 cm² and a maximum diameter of 2.0 cm (4.0 cm²). Target tumors were not to be located within 1.0 cm of the hairline, or on the anogenital area or on the hands or feet, or to have any atypical features. The population ranged from 31 to 89 years of age (median 60 years) and 65% had Fitzpatrick skin type I or II. On a scheduled dosing day, trial cream was applied to the target tumor and approximately 1 cm (about 1/3 inch) beyond the target tumor prior to normal sleeping hours, and 5 times per week dosing was continued for a total of 6 weeks. The target tumor area was clinically assessed 12 weeks after the last scheduled application of trial cream. The entire target tumor was then excised and examined histologically for the presence of tumor.

Efficacy was assessed by the complete response rate defined as the proportion of subjects with clinical (visual) and histological clearance of the sBCC lesion at 12 weeks post-treatment. Of ALDARA-treated subjects, 6% (11/178) who had both clinical and histological assessments post-treatment, and who appeared to be clinically clear had evidence of tumor on excision of the clinically clear treatment area.

Data on composite clearance (defined as both clinical and histological clearance) are shown in Table 12.

Table 12: Composite Clearance Rates at 12 Weeks Post-Treatment for sBCC

Trial	ALDARA	Vehicle
Study sBCC1	70% (66/94)	2% (2/89)
Study sBCC2	80% (73/91)	1% (1/90)
Total	75% (139/185)	2% (3/179)

A separate 5-year, open-label trial was conducted to assess the recurrence of sBCC treated with ALDARA applied topically once daily 5 days per week for 6 weeks. Target tumor inclusion criteria were the same as for the trials described above. At 12 weeks post-treatment, subjects were clinically evaluated for evidence of persistent sBCC (no histological assessment). Subjects with no clinical evidence of sBCC entered the long-term follow-up period. At the 12-week post-treatment assessment, 90% (163/182) of the subjects enrolled had no clinical evidence of sBCC at their target site and 162 subjects entered the long-term follow-up period for up to 5 years. Two-year (24-month) follow-up data are available from this trial and are presented in Table 13.

Table 13: Estimated Clinical Clearance Rates for sBCC in ALDARA-Treated Subjects During Follow-up Period in Open-Label Trial

Follow-up Visit after 12-Week Post-Treatment Assessment	No. of Subjects Who Remained Clinically Clear	No. of Subjects with sBCC Recurrence	No. of Subjects Who Discontinued at This Visit with No sBCCa	Estimated Rate of Subjects Who Clinically Cleared and Remained Clearb
Month 3	153	4	5	87%
Month 6	149	4	0	85%
Month 12	143	2	4	84%
Month 24	139	4	0	79%
a Reasons for discontinuation included death, noncompliance, entry criteria violations, personal reasons, and treatment of nearby sBCC tumor. b Estimated rate of subjects who clinically cleared and remained clear are estimated based on the time to event analysis employing the life table method beginning with the rate of clinical clearance at 12 weeks post-treatment.

External Genital Warts

In a double-blind, placebo-controlled clinical trial, 209 otherwise healthy subjects 18 years and older with EGW were treated with ALDARA, 5% or vehicle applied topically once daily 3 times per week for a maximum of 16 weeks (Study EGW1). The median baseline wart area was 69 mm² (range 8 to 5525 mm²). Subject accountability is shown in the figure below.

Figure 1: Subject Accountability for Study EGW1

Data on complete clearance are listed in Table 14. The median time to complete wart clearance was 10 weeks.

Table 14: Complete Clearance Rates of EGW in Study EGW1

Treatment	Subjects with Complete Clearance of Warts	Subjects without Follow-up	Subjects with Warts Remaining at Week 16
Overall
Aldara (n=109)	54 (50%)	19 (17%)	36 (33%)
Vehicle (n=100)	11 (11%)	27 (27%)	62 (62%)
Females
Aldara (n=46)	33 (72%)	5 (11%)	8 (17%)
Vehicle (n=40)	8 (20%)	13 (33%)	19 (48%)
Males
Aldara (n=63)	21 (33%)	14 (22%)	28 (44%)
Vehicle (n=60)	3 (5%)	14 (23%)	43 (72%)

Patient Information for Aldara

Aldara®
[al dara]
(imiquimod) Cream, 5%

Important: For use on the skin only (topical). Do not use Aldara Cream in your mouth, eyes or vagina.

What is Aldara Cream?

Aldara Cream is a prescription medicine used on the skin (topical) to treat:

• actinic keratosis on the face or scalp in adults with normal immune systems.
• a type of skin cancer called superficial basal cell carcinoma in adults with normal immune systems when surgery is not an option.
• warts on the outside of the genitals (external) and around the outside of the anus (perianal) in people 12 years and older.

It is not known if Aldara Cream is safe and effective in the treatment of:

• people who have weakened immune system.
• people with basal cell nevus syndrome or extreme sensitivity to sunlight (xeroderma pigmentosum).

It is not known if Aldara Cream is safe and effective for the treatment of actinic keratosis or superficial basal cell carcinoma in children less than 18 years of age.

It is not known if Aldara Cream is safe and effective for the treatment of external genital and perianal warts in children below the age of 12.

Before using Aldara Cream, tell your healthcare provider about all of your medical conditions, including if you:

• have problems with your immune system, including long-lasting (chronic) graft versus host disease.
• are being treated or have been treated with other medicines or surgery. You should not use Aldara Cream until your skin has healed from other treatments.
• have other skin problems or sunburn.
• are pregnant or plan to become pregnant. It is not known if Aldara Cream can harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if Aldara Cream passes into your breast milk. If you breastfeed during treatment with Aldara Cream, avoid contact of your treated skin with your baby’s mouth or eyes. Talk to your healthcare provider about the best way to feed your baby if you use Aldara Cream.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How should I use Aldara Cream?

• Use Aldara Cream exactly as prescribed by your healthcare provider.
• Your healthcare provider should show you how to apply Aldara Cream.
• Apply Aldara Cream just before your bedtime.
• Do not use more Aldara Cream than you need to cover the affected area. Using too much Aldara Cream, or using it too often, or for too long can increase your chances for having a severe skin reaction or other side effect.
• After applying Aldara Cream, the opened packet should be thrown away even if all the Aldara Cream was not used.

When using Aldara Cream for actinic keratosis:

• Apply Aldara Cream 2 times per week for 16 weeks. Examples of 2 times per week application schedules are Monday and Thursday, or Tuesday and Friday.
• Aldara Cream should be left on the treated area for about 8 hours. After this time, wash the treated area with mild soap and water to remove Aldara Cream.

When using Aldara Cream for superficial basal cell carcinoma:

• Apply Aldara Cream 1 time a day, for 5 days a week, for example Monday through Friday. Treatment with Aldara Cream should continue for 6 full weeks, even if the superficial basal cell carcinoma appears to be gone.
• Apply Aldara Cream to the superficial basal cell carcinoma and to 1 centimeter (cm) of skin surrounding the treatment area.
• Aldara Cream should be left on the treated area for about 8 hours. After this time, wash the treated area with mild soap and water to remove Aldara Cream.

When using Aldara Cream for external or perianal warts:

• Apply Aldara Cream 3 times per week. Examples of 3 times per week application schedules are Monday, Wednesday and Friday, or Tuesday, Thursday, and Saturday.
• Treatment with Aldara Cream should continue until there is complete clearance of all warts or up to 16 weeks. Aldara Cream will not cure your genital or perianal warts. New warts may develop during treatment with Aldara Cream.
• Uncircumcised males treating warts under their penis foreskin must pull their foreskin back and clean before treatment, and clean daily during the prescribed weeks of treatment.
• Do not get Aldara Cream in the anus when applying to perianal warts.
• Aldara Cream should be left on the treated area for 6 to 10 hours. After this time, wash the treated area with mild soap and water.

Applying Aldara Cream:

• Wash the area where Aldara Cream will be applied with mild soap and water.
• Allow the area to dry for at least 10 minutes.
• Wash your hands well.
• Open a new packet of Aldara Cream just before use.
• Apply a thin layer of Aldara Cream only to the affected area(s) to be treated.
• Rub Aldara Cream in all the way until you cannot see the cream on the affected area(s).
• Wash your hands well after applying Aldara Cream.
• After about 8 hours, wash the treated area(s) with mild soap and water. Do not leave Aldara Cream on your skin longer than prescribed.
• If you forget to apply Aldara Cream, apply the next dose of Aldara Cream at your regularly scheduled time.
• If you get Aldara Cream in your mouth or in your eyes, rinse well with water right away.

What should I avoid while using Aldara Cream?

• Do not cover the treated site with bandages or other closed dressings. Cotton gauze dressings can be used if needed. Cotton underwear can be worn after treating the genital or perianal area.
• Do not use sunlamps or tanning beds, and avoid sunlight as much as possible during treatment with Aldara Cream. Use sunscreen and wear protective clothing if you go outside during daylight.
• Do not have sexual contact including genital, anal, or oral sex when Aldara Cream is on your genital or perianal skin. Aldara Cream may weaken condoms and vaginal diaphragms. This means they may not work as well to prevent pregnancy.

What are the possible side effects of Aldara Cream?

• Treatment site skin reactions. Skin reactions including drainage (weeping) or breakdown of the outer layer of your skin (erosion) can happen after a few applications of Aldara Cream. Swelling outside of the vagina (vulvar swelling) may happen in females. Females should take special care if applying the cream at the opening of the vagina because skin reactions can cause pain or swelling and may cause problems passing urine. If you get skin reactions, wash the treated area with mild soap and water. Stop Aldara Cream right away and call your healthcare provider if you get any skin reactions that affectyour daily activities, or that do not go away.
• Flu-like symptoms. Tell your healthcare provider if you get tiredness, fever, nausea, muscle pain, joint pain, and chills.

Your healthcare provider may temporarily stop or completely stop your treatment with Aldara Cream if you develop treatment site skin reactions of flu-like symptoms.

If you are using Aldara Cream for the treatment of superficial basal cell carcinoma, it is very important to have regular follow-up visits with your healthcare provider to check the area to make sure your skin cancerhas not come back.

The most common side effects of Aldara Cream are skin reactions at the treatment site including:

• redness
• itching
• swelling
• scabbing and crusting
• a sore, blister, or ulcer
• flaking
• burning
• scaling
• skin that becomes hard or thickened
• dryness
• changes in skin color that do not always go away
• skin peeling

Other side effect of Aldara Cream include: headache.

These are not all of the possible side effects of Aldara Cream.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How do I store Aldara Cream?

• Store Aldara Cream at 39°F to 77°F (4°C to 25°C).
• Do not freeze.
• Safely throw away Aldara Cream that is out of date, unused or partially used.

Keep Aldara Cream and all medicines out of reach of children.

General information about the safe and effective use of Aldara Cream.

Medicines are sometimes prescribed for purposes other than those in a Patient Information leaflet. Do not use Aldara Cream for a condition for which it was not prescribed. Do not give Aldara Cream to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Aldara Cream that is written for the health professionals.

What are the ingredients in Aldara Cream?

Active ingredient: imiquimod

Inactive ingredients: benzyl alcohol, cetyl alcohol, glycerin, isostearic acid, methylparaben, polysorbate 60, propylparaben, purified water, sorbitan monostearate, stearyl alcohol, white petrolatum, and xanthan gum.

This Patient Information has been approved by the U.S. Food and Drug Administration.