Imiquimod

Name: Imiquimod

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 Cream or vehicle in 436 subjects enrolled in two double-blind, vehicle-controlled studies. Subjects applied Aldara 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-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-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 Cream and 3 of 220 subjects (1%) on vehicle cream had at least one rest period. Of these Aldara Cream subjects, 32 (91%) resumed therapy after a rest period.

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

Of the 206 Aldara 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 Cream or vehicle in 364 subjects enrolled in two double-blind, vehicle-controlled studies. Subjects applied Aldara 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-Treated Subjects and at a Greater Frequency than with Vehicle in the Combined Studies (Superficial Basal Cell Carcinoma)

Preferred Term Aldara 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 Table 6.

Table 6: Application Site Reactions Reported by > 1% of Aldara-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-treated subjects developed treatment site infections that required a rest period and treatment with antibiotics.

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 Table 8.

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

  Aldara Cream Vehicle
Females (n=114) Males (n=156) Females (n=99) Males (n=157)
All All All All
Grades* Severe Grades* Severe Grades* Severe 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 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 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

Dermal Safety Studies

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

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Aldara 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-Schönlein purpura syndrome

Dosing & Uses

Dosage Forms & Strengths

topical cream

  • 2.5% (Zyclara)
  • 3.75% (Zyclara)
  • 5% (Aldara)

Actinic Keratosis

Indicated for topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on the face or scalp in immunocompetent adults

Zyclara 2.5% or 3.75%: Apply qDay to skin of affected area (either entire face or balding scalp) for two 2-week treatment cycles separated by 2-week no-treatment period

Aldara 5%: Apply 2 times a week for 16 weeks to one defined treatment area (contiguous area <25 cm²); examples of dosing schedules include Monday and Thursday or Tuesday and Friday

Superficial Basal Cell Carcinoma

Target tumor should have maximum <2 cm diameter and be located on trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet); treatment area should include 1 cm margin of skin around tumor

Aldara 5%: Apply 5 times a week for 6 weeks to biopsy-confirmed superficial basal cell carcinoma and include 1 cm margin of skin around tumor

External Genital Warts

Indicated for the treatment of external genital and perianal warts/condyloma acuminata

Zyclara 3.75%: Apply as thin film to entire treatment area and rub in until cream is no longer visible; may wash with mild soap and water after 8 hours of application; use 1 packet or 1 full actuation of pump

Aldara 5%: Apply 3 times a week until total clearance of warts or for a maximum of 16 weeks; examples of application schedules are Monday, Wednesday, Friday or Tuesday, Thursday, Saturday; use 1 packet only for each application

Bladder Cancer (Orphan)

Orphan designation for treatment of carcinoma in situ of the urinary bladder

Sponsor

  • Telormedix SA; Via della Posta 10, CH-6934 Bioggio; SWITZERLAND

Dosing Considerations

Zyclara can be used daily on larger surface areas than Aldara

Actinic keratosis: Do not extend specified treatment cycle due to missed doses or rest periods

Administration

External genital warts: Apply prior to normal sleeping hours and leave on skin for approximately 6-10 hr; then wash with mild soap and water; nonocclusive dressings such as cotton gauze/underwear may be used in management of skin reactions

Do not bandage application area

Wash hands before and after application

Zyclara Pump: Prime before first use only by repeatedly depressing actuator until cream is dispensed

Avoid use in or on lips, nostrils or eyes

Dosage Forms & Strengths

topical cream

  • 3.75% (Zyclara)
  • 5% (Aldara)

External Genital Warts

Indicated for the treatment of external genital and perianal warts/condyloma acuminata

<12 years: Safety and efficacy not established

≥12 years

  • Zyclara 3.75%: Apply as thin film to entire treatment area and rub in until cream is no longer visible; may wash with mild soap and water after 8 hours of application; use 1 packet or 1 full actuation of pump
  • Aldara (5%): Apply 3 times a week until total clearance of warts or for a maximum of 16 weeks; examples of application schedules are Monday, Wednesday, Friday or Tuesday, Thursday, Saturday; use 1 packet only for each application

Administration

External genital warts: Apply prior to normal sleeping hours and leave on skin for approximately 8 hr; then wash with mild soap and water; non-occlusive dressings such as cotton gauze/underwear may be used in management of skin reactions

Warnings

Contraindications

None

Cautions

Avoid or minimize exposure to sunlight, including sunlamps; wear protective clothing

Do not use until skin has fully healed from previous drug or surgical treatment

Avoid use in patients with pre-existing autoimmune conditions

Safety and efficacy not established for other forms of BCC besides sBCC Safety and efficacy not established for sBCC lesions on head, face or anogenital area

Dosage is different for different indications

Avoid sexual contact while cream is on skin

Aldara: Safety when applied to skin area >252 cm in treatment of actinic keratosis have not been determined

Intense local skin reactions including skin weeping or erosion may occur after few applications; may require interruption of dosing

May exacerbate inflammatory skin conditions such as chronic graft versus host disease

Severe local inflammatory reactions of female external genitalia can lead to severe vulvar swelling, which may lead to urinary retention; dosing should be interrupted or discontinued

A transient increase in lesion counts may be observed during treatment

Not recommended for oral, ophtalmic, urethral, intravaginal, cervical, rectal, or intra-anal human papilloma viral disease

Do not use in children aged 2-12 years with molluscum contagiosum due to studies failing to demonstrate efficacy

Safety and efficacy not established in immunosuppressed patients or those with basal cell nevus syndrome or xeroderma pigmentosum

Caution in patients with pre-existing autoimmune conditions

Flu-like signs and symptoms may accompany or precede local skin reactions (eg, fatigue, fever, nausea, malaise, arthralgias, chills); interrupt treatment and reassess

What should i discuss with my healthcare provider before using imiquimod topical (aldara, zyclara, zyclara pump)?

To make sure you can safely take imiquimod topical, tell your doctor if you have any of these other conditions:

  • sunburn or other skin problems;
  • a weak immune system or autoimmune disorder;
  • graft-versus-host disease;
  • if you have recently been treated for actinic keratosis or genital warts with surgery or other medications; or
  • if you have recently received a bone marrow transplant or cord blood transplant.

FDA pregnancy category C. It is not known whether imiquimod topical will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

If you are treating the genital or rectal area with imiquimod topical, avoid sexual activity while the medicine is on your skin. Imiquimod topical can weaken the rubber that condoms or diaphragms are made out of. If you use a condom or diaphragm, these items could break if the rubber weakens, and an unplanned pregnancy could result.

It is not known whether imiquimod topical passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Do not use this medicine on a child younger than 12 years old. Imiquimod topical is for use in treating genital warts in patients who are at least 12 years old. All other uses of this medication are for adults over 18 only.

  • Genital Warts in Men (HPV)
  • Genital Warts in Women (HPV)
  • Psoriasis

Other Requirements

  • Store imiquimod at 39 - 77° F (4 - 25° C). Do not freeze.
  • Safely throw away imiquimod that is out of date or that you do not need.
  • Keep imiquimod and all medicines out of the reach of children.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to imiquimod or any component of the formulation

Usual Adult Dose for Basal Cell Carcinoma

Biopsy-confirmed superficial basal cell carcinoma:
5% cream: Apply topically to target tumor 5 times per week prior to bedtime for a full 6 weeks. Sufficient cream should be applied to cover the treatment area (including a 1 cm margin of skin around the tumor) and it should be rubbed in until the cream disappears. The cream should be left on for approximately 8 hours and then removed by washing with mild soap and water.

Amount of imiquimod topical 5% cream to use:
Target tumor diameter 0.5 to less than 1 cm: 4 mm (diameter) droplet of cream (approximately 10 mg of 5% cream)

Target tumor diameter greater than or equal to 1 to less than 1.5 cm: 5 mm (diameter) droplet of cream (approximately 25 mg of 5% cream)

Target tumor diameter greater than or equal to 1.5 to 2 cm: 7 mm (diameter) droplet of cream (approximately 40 mg of 5% cream)

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). Treatment area should include a 1 cm margin of skin around the tumor.

Usual Pediatric Dose for Condylomata Acuminata

12 years or older:
3.75% cream: Apply a thin layer topically to external genital/perianal warts once a day prior to bedtime. Up to 1 packet may be applied to the treatment area at each application. The cream should be left on for approximately 8 hours and then removed by washing with mild soap and water.

Treatment should continue until total clearance of genital/perianal warts or for up to 8 weeks. The treatment period should not be extended beyond 8 weeks due to rest periods or missed doses.

5% cream: Apply topically to external genital/perianal warts 3 times per week prior to bedtime. The cream should be applied as a thin layer to the wart area and rubbed in until it disappears. The cream should be left on for 6 to 10 hours and then removed by washing with mild soap and water.

Treatment should continue until total clearance of genital/perianal warts or for a maximum of 16 weeks.

Liver Dose Adjustments

Data not available

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