Can Imiquimod cause fatigue?

ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Local Skin Reactions [see Warnings and Precautions ( 5.1 )] • Local Hypopigmentation Reactions [see Warnings and Precautions ( 5.2 )] • Systemic Reactions [see Warnings and Precautions ( 5.3 )] Most common application site or local skin adverse reactions (incidence >28%) are erythema, flaking/scaling/dryness, scabbing/crusting, edema, erosion/ulceration, induration, itching, burning, excoriation, vesicles. Other reported systemic adverse reactions (≥1%): fatigue, fever, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Padagis ® at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 Imiquimod Cream or vehicle in 436 subjects with AK enrolled in two double-blind, vehicle-controlled trials (Studies AK1 and AK2) [see Clinical Studies (14.1)] . Subjects applied Imiquimod Cream, 5% or vehicle topically, to a 25 cm 2 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 Imiquimod-Treated Subjects with AK and at a Greater Frequency than Vehicle in Studies AK1 and AK2 Imiquimod Cream (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 Imiquimod-Treated Subjects with AK and at a Greater Frequency than Vehicle in Studies AK1 and AK2 Imiquimod 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". The incidence and severity of local skin reactions that occurred during controlled trials are shown in Table 4. Table 4: Local Skin Reactions in the Treatment Area of Imiquimod-Treated Subjects with AK as Assessed by the Investigator in Studies AK1 and AK2 Imiquimod 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 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 imiquimod cream and 3 of 220 subjects (1%) on vehicle had at least one rest period. Of the imiquimod-treated subjects, 32 (91%) resumed therapy after a rest period. In the AK trials, 22 of 678 (3.2%) of imiquimod-treated subjects developed treatment site infections that required a rest period off imiquimod cream and were treated with antibiotics (19 with oral and 3 with topical). Of the 206 imiquimod-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 imiquimod cream or vehicle in 364 subjects with sBCC enrolled in two double-blind, vehicle-controlled trials (sBCC1 and sBCC2) [see Clinical Studies ( 14.2 )] . Subjects applied imiquimod cream, 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 Imiquimod-Treated Subjects with sBCC and at a Greater Frequency than Vehicle in Studies sBCC1 and sBCC2 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 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 Imiquimod-Treated Subjects with sBCC and at a Greater Frequency than Vehicle in Studies sBCC1 and sBCC2 Imiquimod 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”. 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 Imiquimod-Treated Subjects with sBCC as Assessed by the Investigator in Studies sBCC1 and sBCC2 Imiquimod 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 trial) were local skin and application site reactions; 10% (19/185) of imiquimod-treated subjects received rest periods. The average number of doses not received per imiquimod-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 imiquimod-treated subjects discontinued for local skin/application site reactions. In the sBCC trials, 17 of 1266 (1.3%) imiquimod-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 ( 14.3 )] , imiquimod cream, 5% was applied topically to EGW in 109 subjects. Selected adverse reactions in imiquimod-treated subjects are listed below

WARNINGS AND PRECAUTIONS Intense local inflammatory reactions can occur (e.g., skin weeping, erosion). Dosing interruption may be required ( 2 , 5.1 , 6 ). 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. Flu-like systemic signs and symptoms including malaise, fever, nausea, myalgias and rigors may occur. Dosing interruption may be required ( 2 , 5.2 , 6 ). Avoid exposure to sunlight and sunlamps. Wear sunscreen daily ( 5.3 ). Safety and efficacy have not been established for repeat courses of treatment to the same area for AK ( 5.4 ). Imiquimod Cream is not recommended for treatment of BCC subtypes other than the superficial variant, i.e., sBCC( 5.5 ). Treatment of urethral, intra-vaginal, cervical, rectal or intra-anal viral disease is not recommended ( 5.6 ). Safety and efficacy in immunosuppressed patients have not been established ( 1.5 ). 5.1 Local Inflammatory Reactions Intense local inflammatory reactions including skin weeping or erosion can occur after few applications of Imiquimod Cream and may require an interruption of dosing [see Dosage and Administration (2) and Adverse Reactions (6) ]. 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 Imiquimod Cream is not recommended until the skin is completely healed from any previous drug or surgical treatment. 5.2 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 [see Adverse Reactions (6) ]. 5.3 Ultraviolet Light Exposure Exposure to sunlight (including sunlamps) should be avoided or minimized during use of Imiquimod Cream because of concern for heightened sunburn susceptibility. Patients should be warned to use protective clothing (e.g., a hat) when using Imiquimod Cream. Patients with sunburn should be advised not to use Imiquimod Cream until fully recovered. Patients who may have considerable sun exposure, e.g., due to their occupation, and those patients with inherent sensitivity to sunlight should exercise caution when using Imiquimod Cream. Imiquimod Cream shortened the time to skin tumor formation in an animal photoco-carcinogenicity study [see Nonclinical Toxicology (13.1) ] . The enhancement of ultraviolet carcinogenicity is not necessarily dependent on phototoxic mechanisms. Therefore, patients should minimize or avoid natural or artificial sunlight exposure. 5.4 Unevaluated Uses: Actinic Keratosis Safety and efficacy have not been established for Imiquimod Cream in the treatment of actinic keratosis with repeated use, i.e., more than one treatment course, in the same area. The safety of Imiquimod Cream applied to areas of skin greater than 25 2 cm (e.g., 5 cm X 5 cm) for the treatment of actinic keratosis has not been established [see Clinical Pharmacology (12.3) ]. 5.5 Unevaluated Uses: Superficial Basal Cell Carcinoma The safety and efficacy of Imiquimod Cream have not been established for other types of basal cell carcinomas (BCC), including nodular and morpheaform (fibrosing or sclerosing) types. Imiquimod Cream is not recommended for treatment of BCC subtypes other than the superficial variant (i.e., sBCC) . Patients with sBCC treated with Imiquimod Cream should have regular followup of the treatment site [see Clinical Studies (14.2) ]. The safety and efficacy of treating sBCC lesions on the face, head and anogenital area have not been established. 5.6 Unevaluated Uses: External Genital Warts Imiquimod Cream has not been evaluated for the treatment of urethral, intra-vaginal, cervical, rectal, or intra-anal human papilloma viral disease.