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.