Product Monograph - Apo-Imiquimod
ACTION AND CLINICAL PHARMACOLOGY
In vitro studies have demonstrated that imiquimod induces the release of interferon alpha (IFN-α) and other cytokines from human monocytes/macrophages and keratinocytes. The panel of cytokines induced varied with the cell's tissue origin. Topical in vivo application of imiquimod cream on mouse skin resulted in increased concentrations of IFN and tumor necrosis factor (TNF) compared with skin of untreated mice. The cytokine inducing properties of imiquimod may be responsible for its activity against genital/perianal warts, as imiquimod does not have a direct antiviral activity in cell cultures. The clinical relevance of these findings is, however, unknown.
Pharmacodynamics
Superficial Basal Cell Carcinoma (sBCC)
The mechanism of action of imiquimod in treating superficial basal cell carcinoma (sBCC) lesions is unknown. One clinical study in 6 subjects has suggested that imiquimod stimulates the infiltration of T-cell lymphocytes, dendritic cells, and macrophages into the basal cell carcinoma lesion.
Actinic Keratosis
The mechanism of action of imiquimod in treating actinic keratosis (AK) lesions is unknown. While the following have been observed, the clinical significance of these observations in AK is not known. In a study of 58 patients with AK treated with imiquimod 3 times per week, the response of biomarkers sensitive to imiquimod after 16 weeks of dosing increased compared to the response after the first dose. For interleukin-1 antagonist, the median concentration observed following multiple dosing was <2-fold higher than that after single dose administration, for interferon-α was ≤3-fold, and for 2′5′-oligoadenylate synthetase was approximately 3-fold.
External Genital Warts
Imiquimod has no direct antiviral activity in cell culture. A study in 22 patients with genital/perianal warts comparing imiquimod and vehicle shows that imiquimod 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
Percutaneous absorption of imiquimod has been studied through intact healthy skin, the skin of genital warts, and lesions of sun damaged skin. Percutaneous absorption of [14C] imiquimod was minimal in a study involving six healthy subjects treated with a single topical application (5 mg) of [14C] imiquimod in cream formulation. No radioactivity was detected in the serum (lower limit of quantitation is 1 ng/mL) and <0.9% of the radiolabeled dose was excreted in the urine and feces following topical application.
Systemic absorption of imiquimod was observed across the affected skin of 12 patients with genital/perianal warts who were treated 3 times per week with sufficient 5% imiquimod cream to cover the affected wart area (average dose 4.6 mg imiquimod) for 16 weeks. Mean (median) peak drug concentrations of 0.3 (0.1) ng/mL were seen following week 16 dosing. Mean (median) urinary recoveries following the last dose of week 16, expressed as percent of the estimated applied dose, were 0.24 (0.09) and 2.52 (1.2) % of the dose for males and females, respectively, which may suggest a possible sex difference in absorption and/or excretion.
Similarly, systemic absorption of imiquimod across the affected skin of 58 patients with AK was observed with a dosing frequency of 3 applications per week for 16 weeks. Mean (median) peak serum drug concentrations at the end of week 16 were observed between 9 and 12 hours and were approximately 0.1 (0.1), 0.2 (0.2), and 3.5 (1.6) ng/mL for the applications to face (12.5 mg imiquimod, 1 single-use packet), scalp (25 mg, 2 packets) and hands/arms (75 mg, 6 packets), respectively. The application surface area was not controlled in the scalp and hands/arms groups. Dose proportionality was not observed, although the pharmacokinetic parameters (Cmax and AUC) tended to increase with dose. It appears that systemic exposure may be more dependent on surface area of application than amount of applied dose. The apparent half-life following topical dosing was calculated as 26 hours, which is approximately 10 times greater than the 2-hour apparent half-life seen following subcutaneous dosing and suggests prolonged retention of drug in the skin. Mean (median) urinary recoveries at week 16 were 0.18 (0.14), 0.24 (0.24) and 0.12 (0.09) % of the applied dose following application to the face, scalp and hands/arms, respectively. The highest urinary recovery measured in any patient was less than 0.6% of the applied dose at week 16.
Comparative Clinical Bioequivalence Study
The purpose of this study was to determine the therapeutic equivalence of APO-IMIQUIMOD Cream, 5% (Apotex Inc.) with Aldara™ (Imiquimod) Cream, 5% (3M Pharmaceuticals Canada), in the treatment of subjects with Actinic Keratosis (AK), using 90% confidence interval of the difference and a 20% equivalence margin.
A double-blind, randomized, vehicle-controlled, multi-centre, parallel-group study was conducted in adult male and female subjects, at least 18 years of age, with 4 to 8 nonhyperkeratotic, nonhypertrophic AK lesions located within a contiguous 25 cm2 area on the face or balding scalp. Patients applied study medication to the target treatment area twice weekly for 16 weeks and the primary efficacy endpoint was the complete clearance rate of AK lesions at Week 24 (8 weeks post-treatment). The efficacy results are summarized in the following table:
Complete Clearance Rate at Week 24 in Patients with Actinic Keratosis
| Study Population Characteristic | Imiquimod 5% | AldaraTM 5% | Vehicle |
| Per Protocol Population | |||
| N | 106 | 100 | 63 |
| Number and percent of patients with complete clearance at Week 24 | 49 (46.2%) | 48 (48.0%) | 9 (14.3%) |
| Difference (vs AldaraTM) a | -1.8% | ||
| 90% CI b | (-14.2%, 10.6%) | ||
| Modified Intent to Treat Population | |||
| N | 141 | 139 | 72 |
| Number and percent of patients with complete clearance at Week 24, using LOCF c | 62 (44.0%) | 55 (39.6%) | 9 (12.5%) |
| Difference (vs AldaraTM) a | 4.4% | ||
| 90% CI b | (-6.0%, 14.8%) | ||
| Difference (vs vehicle) d | 31.5% | 27.1% | |
| p-value (vs vehicle) e | <0.0001 | <0.0001 |
NOTE: Complete clearance rate is the proportion of subjects with no clinically visible AK lesions within treatment target area at Week 24.
NOTE: Demonstrating therapeutic equivalence of the test formulation vs. reference treatment is based on the complete clearance rate at Week 24.
NOTE: The test for superiority of active treatment over the vehicle treatment is based on the complete clearance rate at Week 24. a. Difference is the subtraction of the complete clearance rate at Week 24 of reference treatment from the test treatment. b. 90% confidence interval of the difference calculated by Wald's Method with Yate's Continuity Correction. c. LOCF: last-observation-carried-forward
d. Difference is the subtraction of the complete clearance rate at Week 24 of vehicle from each active treatment. e. P-value comes from a Continuity-Corrected Z-Test.
APO-IMIQUIMOD cream 5% demonstrated therapeutic equivalence to Aldara™ 5% in complete clearance rate of lesions in subjects with Actinic Keratosis.
INDICATIONS AND CLINICAL USE
APO-IMIQUIMOD (imiquimod) cream is indicated in immunocompetent adults for the following conditions.
- Treatment of biopsy-confirmed, primary superficial basal cell carcinoma (sBCC) with a maximum tumor diameter of 2.0 cm, located on the trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet), otherwise amenable to simple surgical excision, in patients who, in consultation with their physician, choose not to have surgery and are willing to undergo regular follow-up. Note: Surgical excision is the usual treatment of choice for these sBCC tumors. While imiquimod cream has been shown to be effective in the short-term clearance of sBCC in ~75% of cases, there are no data directly comparing imiquimod cream to surgical excision.
- Treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratosis on the face or balding scalp.
- Treatment of external genital and perianal warts/condyloma acuminata.
CONTRAINDICATIONS
APO-IMIQUIMOD (imiquimod) cream is contraindicated in individuals with a history of sensitivity reactions to any of its components. It should be discontinued if hypersensitivity to any of its ingredients is noted.
WARNINGS
Patients with sBCC treated with imiquimod cream are required to have regular follow-up of the treatment site because the efficacy of imiquimod in the treatment of sBCC is generally less than that with surgery and, as well, because the long-term efficacy and safety of imiquimod in the treatment of sBCC have not yet been established.
The histological diagnosis of superficial basal cell carcinoma should be established prior to treatment since imiquimod cream has not been evaluated for the treatment of other types of basal cell carcinomas, including nodular, morpheaform (fibrosing or sclerosing) types and is not recommended for treatment of BCC subtypes other than the superficial variant.
Imiquimod cream has not been evaluated for the treatment of sBCC on the face, head, hands or feet, and anogenital area.
The efficacy of imiquimod cream in the prevention of squamous cell carcinoma (SCC) associated with AK has not been established. One subject who participated in a clinical trial of imiquimod and had complete clearance of AK lesions with imiquimod treatment developed a SCC in situ in the treatment area within 12 to 18 months of treatment (see PHARMACOLOGY, Clinical Studies).
Imiquimod cream has not been evaluated for the treatment of urethral, intra-vaginal, cervical, rectal, or intra-anal human papilloma viral disease and is not recommended for these conditions.
Hypersensitivity reactions (urticaria) and erythema multiforme have been reported in patients receiving imiquimod cream. Causality has not been established and no other reports of similar cases have been reported in post-marketing surveillance. Imiquimod cream should be discontinued immediately if these events occur.
Some reports of localized hypopigmentation and hyperpigmentation following use of imiquimod cream have been received. Post-marketing reporting suggests that these skin color changes may be permanent in some patients.
PRECAUTIONS
General
Imiquimod cream administration is not recommended until skin or genital/perianal tissue is healed from any previous drug or surgical treatment. Imiquimod cream has the potential to exacerbate inflammatory conditions of the skin.
Local skin reactions such as erythema, erosion, excoriation/flaking, and edema are common.
Should a severe local skin reaction occur, the cream should be removed by washing the treatment area with mild soap and water. Treatment with imiquimod cream can be resumed after the skin reaction has subsided.
The efficacy and safety of imiquimod cream have not been established for patients with Basal Cell Nevus Syndrome or Xeroderma Pigmentosum.
The safety of imiquimod cream applied to areas of skin greater than 25 cm2 for the treatment of actinic keratosis has not been established.
The safety and efficacy of imiquimod cream in immunosuppressed patients have not been established.
Flu-like systemic signs and symptoms including malaise, fever, nausea, myalgias and rigors may occur. Dosing interruption may be required.
Imiquimod cream should be used with caution in patients with pre-existing autoimmune conditions. Rare reports have been received of exacerbation of autoimmune conditions in patients treated with imiquimod cream.
Imiquimod cream has the potential to exacerbate inflammatory conditions of the skin, including chronic graft versus host disease.
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 (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. Phototoxicity has not been adequately assessed for imiquimod cream. The enhancement of ultraviolet carcinogenicity is not necessarily dependent on phototoxic mechanisms. Despite the absence of observed phototoxicity in humans (see PHARMACOLOGY, Clinical Studies), imiquimod cream shortened the time to skin tumor formation in an animal photoco-carcinogenicity study (see Carcinogenesis, Mutagenesis, Impairment of Fertility). Therefore, it is prudent for patients to minimize or avoid natural or artificial sunlight exposure.
Carcinogenicity, Mutagenesis, and Impairment of Fertility
Two-year bioassays in Wistar rats (up to 3 mg/kg orally per day) and CD-1 mice (up to 4.5 mg/kg applied topically 3 times per week) showed no evidence of a carcinogenic effect in male and female rats and female mice. Liver tumors were increased in male mice exposed to the highest dose concentration, compared to the unexposed controls. However, the number of tumors was within the range seen historically for male CD-1 mice. It is generally accepted that an increase in liver tumors in male mice, in the absence of other neoplastic responses in mice or rats, is not indicative of a carcinogenic risk for humans.
In a photocarcinogenicity study in hairless mice, animals received imiquimod cream 3 times per week at imiquimod concentrations of 0.03%, 0.1% and 0.3% and were irradiated with solar ultraviolet light for 5 days each week for 40 weeks and observed an additional 12 weeks. Vehicle cream enhanced UVR-induced skin tumour development. Imiquimod cream had no additional effect on tumour development beyond the vehicle effect (i.e., the addition of the active ingredient, imiquimod, to the vehicle cream did not result in an additional effect beyond the vehicle effect on tumour development).
Pregnancy
Imiquimod was not teratogenic in rat or rabbit teratology studies. In rats at a high maternally toxic dose (28 times human dose on a mg/m2 basis), reduced pup weights and delayed ossification were observed. However, there are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
It is not known whether topically applied imiquimod is excreted in breast milk.
Use in Children
Safety and efficacy in patients below the age of 18 years have not been established.
Geriatric Use
Although no overall differences in safety or effectiveness have been observed between elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. Of the 185 patients in the 5 times per week treatment groups of clinical studies evaluating the treatment of sBCC with imiquimod cream, 65 patients (35%) were 65 years and older, while 25 patients (14%) were 75 years and older. Of the 215 patients in the 2 times per week clinical studies evaluating the treatment of AK lesions with imiquimod cream, 127 patients (59%) were 65 years and older, while 60 patients (28%) were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. No other clinical experience has identified differences in responses between the elderly and younger patients.
DRUG INTERACTIONS
Interactions between imiquimod cream with other drugs have not been established.
As an immune response modifier, imiquimod is not recommended for use concurrently with immunosuppressive drugs such as tacrolimus, pimecrolimus, mycophenolate mofetil, cyclosporine or methotrexate.
Concomitant use of corticosteroids with imiquimod may potentially limit efficacy.
ADVERSE REACTIONS
Superficial Basal Cell Carcinoma
The data described below reflect exposure to imiquimod cream or vehicle in 364 patients enrolled in two double-blind, vehicle-controlled studies in which subjects with sBCC applied imiquimod cream or vehicle to the target lesions 5X/week for 6 weeks.
Summary of All Adverse Events Reported by >1% of Patients in the Combined 5X/Week Studies | ||||
BODY SYSTEM PREFERRED TERM | Imiquimod 5X/Week (n = 185) | Vehicle 5X/Week (n = 179) | ||
APPLICATION SITE DISORDERS APPLICATION SITE REACTION | 52 | (28.1%) | 5 | (2.8%) |
BODY AS A WHOLE - GENERAL DISORDERS ALLERGY AGGRAVATED BACK PAIN CHEST PAIN FATIGUE FEVER PAIN | 2 7 2 4 3 3 | (1.1%) (3.8%) (1.1%) (2.2%) (1.6%) (1.6%) | 1 1 0 2 0 2 | (0.6%) (0.6%) (0.0%) (1.1%) (0.0%) (1.1%) |
CARDIOVASCULAR DISORDERS, GENERAL HYPERTENSION | 5 | (2.7%) | 1 | (0.6%) |
CENTRAL AND PERIPHERAL-NERVOUS SYSTEM DISORDERS DIZZINESS HEADACHE | 2 14 | (1.1%) (7.6%) | 1 4 | (0.6%) (2.2%) |
GASTRO-INTESTINAL SYSTEM DISORDERS ABDOMINAL PAIN DIARRHOEA DYSPEPSIA GASTRO-INTESTINAL DISORDER NOS NAUSEA TOOTH DISORDER | 1 1 3 1 2 0 | (0.5%) (0.5%) (1.6%) (0.5%) (1.1%) (0.0%) | 2 2 2 2 0 2 | (1.1%) (1.1%) (1.1%) (1.1%) (0.0%) (1.1%) |
METABOLIC AND NUTRITIONAL DISORDERS GOUT | 2 | (1.1%) | 0 | (0.0%) |
MUSCULO-SKELETAL SYSTEM DISORDERS SKELETAL PAIN | 3 | (1.6%) | 2 | (1.1%) |
PSYCHIATRIC DISORDERS ANXIETY | 2 | (1.1%) | 1 | (0.6%) |
RESISTANCE MECHANISM DISORDERS INFECTION INFECTION FUNGAL | 1 2 | (0.5%) (1.1%) | 3 2 | (1.7%) (1.1%) |
RESPIRATORY SYSTEM DISORDERS COUGHING PHARYNGITIS RHINITIS SINUSITIS UPPER RESPIRATORY TRACT INFECTION | 3 2 5 4 6 | (1.6%) (1.1%) (2.7%) (2.2%) (3.2%) | 1 1 1 1 2 | (0.6%) (0.6%) (0.6%) (0.6%) (1.1%) |
SECONDARY TERMS INFLICTED INJURY PROCEDURAL SITE REACTION | 3 2 | (1.6%) (1.1%) | 3 3 | (1.7%) (1.7%) |
SKIN AND APPENDAGE DISORDERS HYPERKERATOSIS RASH SKIN DISORDER | 3 3 1 | (1.6%) (1.6%) (0.5%) | 2 1 3 | (1.1%) (0.6%) (1.7%) |
Summary of All Adverse Events Reported by >1% of Patients in the Combined 5X/Week Studies | ||||
BODY SYSTEM PREFERRED TERM | Imiquimod 5X/Week (n = 185) | Vehicle 5X/Week (n = 179) | ||
WHITE CELL AND RESISTANCE DISORDER LYMPHADENOPATHY | 5 | (2.7%) | 1 | (0.6%) |
The most frequently reported adverse reactions were those of local skin and application site reactions including erythema, edema, induration, erosion, flaking/scaling, scabbing/crusting, itching and burning at the application site. 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 patients received rest periods. The average number of doses not received per patient due to rest periods was 7 doses with a range of 2 to 22 doses; 79% of patients (15/19) resumed therapy after a rest period. Overall, in the clinical studies, 2% (4/185) of patients discontinued for local skin/application site reactions. The incidence of application site reactions reported by >1% of the subjects during the 6-week treatment period is summarized in the table below.
Summary of All Application Site Reactions Reported by >1% of Patients in the Combined 5X/Week Studies | ||||
| Included Term | Imiquimod 5X/Week (n = 185) | Vehicle 5X/Week (n = 179) | ||
ITCHING AT TARGET SITE BURNING AT TARGET SITE PAIN AT TARGET SITE TENDERNESS AT TARGET SITE ERYTHEMA AT REMOTE SITE PAPULE(S) AT TARGET SITE BLEEDING AT TARGET SITE TINGLING AT TARGET SITE INFECTION AT TARGET SITE | 30 11 6 2 3 3 4 1 2 | (16.2%) (5.9%) (3.2%) (1.1%) (1.6%) (1.6%) (2.2%) (0.5%) (1.1%) | 1 2 0 0 0 0 0 2 0 | (0.6%) (1.1%) (0.0%) (0.0%) (0.0%) (0.0%) (0.0%) (1.1%) (0.0%) |
Local skin reactions were collected independently of the adverse event "application site reaction" in an effort to provide a better picture of the specific types of local reactions that might be seen. The incidence and severity of local skin reactions that occurred during controlled studies are shown in the following table.
Most Intense Local Skin Reactions in the Treatment Area as Assessed by the Investigator (Percentage of Patients) 5X/Week Application | ||||
| Local Skin Reaction | Mild/Moderate | Severe | ||
Imiquimod Cream n = 184 | Vehicle n = 178 | Imiquimod Cream n = 184 | Vehicle n = 178 | |
| EDEMA | 71% | 36% | 7% | 0% |
| EROSION | 54% | 14% | 13% | 0% |
| ERYTHEMA | 69% | 95% | 31% | 2% |
| FLAKING/SCALING | 87% | 76% | 4% | 0% |
| INDURATION | 78% | 53% | 6% | 0% |
| SCABBING/CRUSTING | 64% | 34% | 19% | 0% |
| ULCERATION | 34% | 3% | 6% | 0% |
| VESICLES | 29% | 2% | 2% | 0% |
Adverse events judged to be probably or possibly related to imiquimod cream and reported by at least 1% of the patients included:
Application Site Reactions: Target Site Reactions (itching, burning, pain, tenderness, bleeding, papules, infection, pimples)
Remote Site Reactions: erythema
Body as a Whole: back pain
White Cell and Resistance Disorders: lymphadenopathy.
In the sBCC studies, 23 of 1266 (1.8%) imiquimod-treated patients developed treatment site infections that were treated with antibiotics; the majority of these patients required a rest period off imiquimod cream. In all vehicle-controlled BCC studies, the adverse event lymphadenopathy was reported in 12 (1.8%) of the 672 imiquimod-treated patients. In all phase II/III BCC trials with 5X/week imiquimod dose groups, 9 (1.7%) of 518 patients with pre- and post-treatment laboratory tests developed a ≥2 toxicity grade level shift from baseline to end-of-treatment in absolute lymphocyte counts.
Actinic Keratosis
The data described below reflect exposure to imiquimod cream or vehicle in 436 patients enrolled in two double-blind, vehicle-controlled studies in which patients applied imiquimod cream or vehicle to a 25 cm2 contiguous treatment area on the face or balding scalp 2 times per week for 16 weeks.
In controlled clinical studies, the most frequently reported adverse reactions were those of local skin and application site reactions including erythema, flaking/scaling/dryness, scabbing/crusting, itching and burning at the application site. The adverse reactions that most frequently resulted in clinical intervention (e.g., rest periods, withdrawal from study) were local skin and application site reactions: 16% (35/215) of patients received rest periods. The average number of doses not received per patient due to rest periods was 4 doses with a range of 1 to 11 doses: 91% of patients (32/35) resumed therapy after a rest period. Overall, in the clinical studies, 2% (5/215) of patients discontinued for local skin/application site reactions and one patient discontinued due to the development of urticaria. One patient developed a bacterial infection at the treatment site.
Summary of All Adverse Events Reported by >1% of Patients in the Combined 2X/Week Studies | ||||
BODY SYSTEM PREFERRED TERM | Imiquimod 2X/Week (n = 215) | Vehicle 2X/Week (n = 221) | ||
APPLICATION SITE DISORDERS APPLICATION SITE REACTION | 71 | (33.0%) | 32 | (14.5%) |
BODY AS A WHOLE - GENERAL DISORDERS BACK PAIN FATIGUE FEVER HEADACHE HERNIA NOS INFLUENZA-LIKE SYMPTOMS PAIN RIGORS | 3 3 3 11 4 4 3 3 | (1.4%) (1.4%) (1.4%) (5.1%) (1.9%) (1.9%) (1.4%) (1.4%) | 2 2 0 7 1 4 3 0 | (0.9%) (0.9%) (0.0%) (3.2%) (0.5%) (1.8%) (1.4%) (0.0%) |
CARDIOVASCULAR DISORDERS, GENERAL CHEST PAIN HYPERTENSION | 1 3 | (0.5%) (1.4%) | 4 5 | (1.8%) (2.3%) |
CENTRAL AND PERIPH-ERAL NERVOUS SYSTEM DISORDERS DIZZINESS | 3 | (1.4%) | 1 | (0.5%) |
GASTRO-INTESTINAL SYSTEM DISORDERS DIARRHOEA DYSPEPSIA GASTROESOPHAGEAL REFLUX NAUSEA VOMITING | 6 6 3 3 3 | (2.8%) (2.8%) (1.4%) (1.4%) (1.4%) | 2 4 3 3 1 | (0.9%) (1.8%) (1.4%) (1.4%) (0.5%) |
| HEART RATE AND RHYTHM DISORDERS FIBRILLATION ATRIAL | 3 | (1.4%) | 2 | (0.9%) |
METABOLIC AND NUTRITIONAL DISORDERS HYPERCHOLESTEROLAEMIA | 4 | (1.9%) | 0 | (0.0%) |
MUSCULO-SKELETAL SYSTEM DISORDERS ARTHRALGIA ARTHRITIS MYALGIA SKELETAL PAIN | 2 2 3 1 | (0.0%) (0.9%) (1.4%) (0.5%) | 4 3 3 3 | (1.8%) (1.4%) (1.4%) (1.4%) |
NEOPLASM BASAL CELL CARCINOMA CARCINOMA SQUAMOUS | 5 8 | (2.3%) (3.7%) | 5 5 | (2.3%) (2.3%) |
RESISTANCE MECHANISM DISORDERS HERPES SIMPLEX INFECTION VIRAL | 9 4 3 | (4.2%) (1.9%) (1.4%) | 11 4 2 | (5.0%) (1.8%) (0.9%) |
RESPIRATORY SYSTEM DISORDERS BRONCHITIS COUGHING PHARYNGITIS PULMONARY CONGESTION RHINITIS SINUSITIS | 2 6 4 1 7 16 | (0.9%) (2.8%) (1.9%) (0.5%) (3.3%) (7.4%) | 3 10 4 3 8 14 | (1.4%) (4.5%) (1.8%) (1.4%) (3.6%) (6.3%) |
Summary of All Adverse Events Reported by >1% of Patients in the Combined 2X/Week Studies | ||||
BODY SYSTEM PREFERRED TERM | Imiquimod 2X/Week (n = 215) | Vehicle 2X/Week (n = 221) | ||
| UPPER RESPIRATORY TRACT INFECTION | 33 | (15.3%) | 27 | (2.2%) |
SECONDARY TERMS ABRASION NOS CYST NOS INFLICTED INJURY POST-OPERATIVE PAIN | 7 0 19 3 | (3.3%) (0.0%) (8.8%) (1.4%) | 5 4 21 4 | (2.3%) (1.8%) (9.5%) (1.8%) |
SKIN AND APPENDAGES DISORDERS ALOPECIA DERMATITIS ECZEMA HYPERKERATOSIS PHOTOSENSITIVITY REACTION PRURITUS RASH SKIN DISORDER VERRUCA | 47 3 3 4 19 2 2 5 6 1 | (21.9%) (1.4%) (1.4%) (1.9%) (8.8%) (0.9%) (0.9%) (2.3%) (2.8%) (0.5%) | 42 0 7 3 12 4 3 5 7 3 | (19.0%) (0.0%) (3.2%) (1.4%) (5.4%) (1.8%) (1.4%) (2.3%) (3.2%) (1.4%) |
| URINARY SYSTEM DISORDERS URINARY TRACT INFECTION | 8 3 | (3.7%) (1.4%) | 10 1 | (4.5%) (0.5%) |
VISION DISORDERS CONJUNCTIVITIS EYE ABNORMALITY EYE INFECTION | 1 4 0 | (0.5%) (1.9%) (0.0%) | 3 1 3 | (1.4%) (0.5%) (1.4%) |
Summary of All Application Site Reactions Reported by >1% of Patients in the Combined 2X/Week Studies | ||||
| Included Term | Imiquimod 2X/Week (n = 215) | Vehicle 2X/Week (n = 221) | ||
BLEEDING AT TARGET SITE BURNING AT REMOTE SITE BURNING AT TARGET SITE INDURATION AT REMOTE SITE INDURATION AT TARGET SITE IRRITATION AT REMOTE SITE ITCHING AT REMOTE SITE ITCHING AT TARGET SITE PAIN AT TARGET SITE STINGING AT TARGET SITE TENDERNESS AT TARGET SITE | 7 4 12 3 5 3 7 44 5 6 4 | (3.3%) (1.9%) (5.6%) (1.4%) (2.3%) (1.4%) (3.3%) (20.5%) (2.3%) (2.8%) (1.9%) | 1 0 4 0 3 0 3 15 2 2 3 | (0.5%) (0.0%) (1.8%) (0.0%) (1.4%) (0.0%) (1.4%) (6.8%) (0.9%) (0.9%) (1.4%) |
Local skin reactions were collected independently of the adverse event "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.
Most Intense Local Skin Reactions in the Treatment Area as Assessed by the Investigator (Percentage of Patients) 2X/Week Application | ||||
| Event | Mild/Moderate | Severe | ||
Imiquimod Cream (n = 215) | Vehicle (n = 220) | Imiquimod Cream (n = 215) | Vehicle (n = 220) | |
| Erythema | 80% | 91% | 18% | 2% |
| Edema | 49% | 10% | 0% | 0% |
| Weeping/Exudate | 21% | 1% | 0% | 0% |
| Vesicles | 9% | 1% | 0% | 0% |
| Erosion/Ulceration | 46% | 9% | 2% | 0% |
| Flaking/Scaling/Dryness | 85% | 87% | 7% | 3% |
| Scabbing/Crusting | 70% | 40% | 8% | 2% |
External Genital Warts
In controlled clinical trials, the most frequently reported adverse reactions were those of local skin and application site reactions; some patients also reported systemic reactions. These reactions were usually mild to moderate in intensity; however, severe reactions were reported with 3 times per week application. These reactions were more frequent and more intense with daily application than with 3 times per week application. Overall, in the 3 times per week application clinical studies, 1.2% (4/327) of the patients 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.
| Wart Site Reaction as Assessed by Investigator (3X/Week Application) | ||||||||
| Mild/Moderate | Severe | |||||||
| Females | Males | Females | Males | |||||
| Imiquimod Cream (n = 114) | Vehicle (n = 99) | Imiquimod Cream (n = 156) | Vehicle (n = 157) | Imiquimod Cream (n = 114) | Vehicle (n = 99) | Imiquimod Cream (n = 156) | Vehicle (n = 157) | |
| Erythema | 61% | 21% | 54% | 22% | 4% | 0% | 4% | 0% |
| Erosion | 30% | 8% | 29% | 6% | 1% | 0% | 1% | 0% |
| Excoriation/ Flaking | 18% | 8% | 25% | 8% | 0% | 0% | 1% | 0% |
| Edema | 17% | 5% | 12% | 1% | 1% | 0% | 0% | 0% |
| Induration | 5% | 2% | 7% | 2% | 0% | 0% | 0% | 0% |
| Ulceration | 5% | 1% | 4% | 1% | 3% | 0% | 0% | 0% |
| Scabbing | 4% | 0% | 13% | 3% | 0% | 0% | 0% | 0% |
| Vesicles | 3% | 0% | 2% | 0% | 0% | 0% | 0% | 0% |
Remote site skin reactions were also reported in female and male patients treated 3 times a week with imiquimod cream. 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%).
Adverse events judged to be probably or possibly related to imiquimod cream reported by more than 5% of patients are listed below; also included are soreness, influenza-like symptoms and myalgia.
| Adverse Events Probably or Possibly Related to Imiquimod Cream (3X/Week Application) | ||||
| Females | Males | |||
| Imiquimod Cream (n = 117) | Vehicle (n = 103) | Imiquimod Cream (n = 156) | Vehicle (n = 158) | |
| APPLICATION SITE DISORDERS: | ||||
| APPLICATION SITE REACTIONS Wart Site: | ||||
| Itching | 32% | 20% | 22% | 10% |
| Burning | 26% | 12% | 9% | 5% |
| Pain | 8% | 2% | 2% | 1% |
| Soreness | 3% | 0% | 0% | 1% |
| FUNGAL INFECTIONa | 11% | 3% | 2% | 1% |
| SYSTEMIC REACTIONS: | ||||
| Headache | 4% | 3% | 5% | 2% |
| Influenza-like symptoms | 3% | 2% | 1% | 0% |
| Myalgia | 1% | 0% | 1% | 1% |
aIncidences reported without regard to causality with imiquimod cream.
Adverse events judged to be possibly or probably related to imiquimod cream and reported by more than 1% of patients include:
Application Site Disorders: Wart Site Reactions (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.
Post-Marketing Experience
Application Site Disorders (resulting from internal application): local skin reactions, pain and swelling, difficulty passing urine in female patients.
Rare reports have been received of either the onset or exacerbation of autoimmune conditions (including thyroiditis, multiple sclerosis, spondyloarthropathy, psoriasis, ulcerative colitis) in association with imiquimod cream therapy.
The following adverse reactions have been identified during post-approval use of imiquimod cream, 5%. 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.
Skin and Appendages: exfoliative dermatitis, erythema multiforme, hyperpigmentation, hypertrophic scar.
Vascular: Henoch-Schoenlein purpura syndrome.
SYMPTOMS AND TREATMENT OF OVERDOSAGE
Overdosage of imiquimod cream in humans is unlikely due to minimal percutaneous absorption. Animal studies reveal a rabbit dermal lethal imiquimod dose of greater than 5000 mg/kg. Persistent topical overdosing of imiquimod cream could result in severe local skin reactions.
The most clinically serious adverse event reported following multiple oral imiquimod doses of ≥200 mg was hypotension which resolved following oral or intravenous fluid administration.
DOSAGE AND ADMINISTRATION
The application frequency for APO-IMIQUIMOD (imiquimod cream) is different for each indication.
Superficial Basal Cell Carcinoma
APO-IMIQUIMOD (imiquimod cream) is to be applied to a biopsy-confirmed sBCC 5 times per week, prior to normal sleeping hours, and left on the skin for approximately 8 hours. The treatment area should include a 1 cm margin of skin around the tumour. The amount of cream to be applied depends upon the diameter of the target sBCC (see table below)
| Patient Dosing Guide | ||
| Target Tumour Diameter | Size of Cream Droplet to be Used (Diameter) | Approximate Amount of Cream 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 |
Before applying the cream, the patient should wash the treatment area with mild soap and water and allow the area to dry thoroughly. The cream should be applied to cover the treatment area, including one centimetre of skin surrounding the tumour, and should be rubbed into the treatment area until the cream is no longer visible. Caution subjects to avoid contacting the cream in or near the eyes. Approximately 8 hours after applying APO-IMIQUIMOD, cream should be removed by washing the area with mild soap and water. An example of a 5 times per week application schedule is to apply APO-IMIQUIMOD cream once per day, Monday through Friday, prior to sleeping hours.
APO-IMIQUIMOD cream treatment should continue for 6 weeks. Local skin reactions in the treatment area are common. Patients should contact their physician if they experience any sign or symptom in the treatment area that restricts or prohibits their daily activity or makes continued application of the cream difficult. A rest period of several days may be taken if required by the patient's discomfort or severity of the local skin reaction. However, the treatment period should not be extended beyond 6 weeks due to missed doses or rest periods.
The technique for proper dose administration should be demonstrated by the prescriber to maximize the benefit of APO-IMIQUIMOD cream therapy. Hand washing before and after cream application is recommended. The application site is not to be occluded.
A follow-up visit at approximately 12 weeks post-treatment to assess the treatment site for clinical clearance is appropriate. Early clinical clearance cannot be adequately assessed until resolution of local skin reactions. If there is clinical evidence of persistent tumour at the 12-week post-treatment visit, a biopsy or other alternative intervention should be considered; the safety of and efficacy of a repeat course of imiquimod cream treatment have not been established. If any suspicious lesion arises in the treatment area at any time after 12 weeks, the patient should seek a medical evaluation.
APO-IMIQUIMOD cream is packaged in single-use packets which contain 250 mg of the cream. No more than one sixth of a packet of APO-IMIQUIMOD cream should be applied to the treatment area at each application. Partially-used packets should be discarded and not reused.
Actinic Keratosis
APO-IMIQUIMOD cream is to be applied 2 times per week to a defined treatment area on the face or scalp no larger than 25 cm2, prior to normal sleeping hours, and left on the skin for approximately 8 hours. Before applying the cream, the patient should wash the treatment area with mild soap and water and allow the area to dry thoroughly. The cream should be rubbed into the treatment area until the cream is no longer visible. Contact with the eyes, lips and nostrils should be avoided. Following the treatment period, cream should be removed by washing the area with mild soap and water. Examples of two times per week application schedules are Monday and Thursday, or Tuesday and Friday prior to sleeping hours.
APO-IMIQUIMOD cream treatment should continue for 16 weeks. Local skin reactions in the treatment area are common. Patients should contact their physician if they experience any sign or symptom in the treatment area that restricts or prohibits their daily activity or makes continued application of the cream difficult. A rest period of several days may be taken if required by the patient's discomfort or severity of the local skin reaction. However, the treatment period should not be extended beyond 16 weeks due to missed doses or rest periods.
The technique for proper dose administration should be demonstrated by the prescriber to maximize the benefit of APO-IMIQUIMOD cream therapy. Hand washing before and after cream application is recommended.
APO-IMIQUIMOD cream is packaged in single-use packets. No more than one packet of APO-IMIQUIMOD cream should be applied to the treatment area at each application. Partially-used packets should be discarded and not reused. The application site is not to be occluded.
External Genital Warts
APO-IMIQUIMOD (imiquimod) cream is to be applied 3 times per week, prior to normal sleeping hours, and left on the skin for 6 to 10 hours. Following the treatment period cream should be removed by washing the treated area with mild soap and water. Examples of 3 times per week application schedules are: Monday, Wednesday, Friday; or Tuesday, Thursday, Saturday application prior to sleeping hours.
APO-IMIQUIMOD cream treatment should continue until there is total clearance of the genital/perianal warts or for a maximum of 16 weeks. Local skin reactions (erythema) at the treatment site are common. A rest period of several days may be taken if required by the patient due to discomfort or severity of the local skin reaction. Treatment may resume once the reaction subsides. Non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions.
The technique for proper dose administration should be demonstrated by the prescriber to maximize the benefit of APO-IMIQUIMOD cream therapy. Hand washing before and after cream application is recommended.
APO-IMIQUIMOD cream is packaged in single-use packets which contain sufficient cream to cover a wart area of up to 20 cm2; use of excessive amounts of cream should be avoided. Patients self-administer APO-IMIQUIMOD cream by applying the cream to external genital and/or perianal warts. A thin layer is applied to the wart area and rubbed in until the cream is no longer visible. The application site is not to be occluded.
N H 2
N
N N PHARMACEUTICAL INFORMATION
Drug Substance:
Proper Name: Imiquimod (USAN, INN)
Chemical Name: 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine
Structural Formula:
Molecular Formula: C14H16N4
Molecular Weight: 240.3 g/mol
Description: White to off-white crystalline powder.
Solubility: Insoluble in water, methanol and acetonitrile but soluble in dimethylsulfoxide (3 mg/mL) and dimethyl formamide.
pKa Value: 7.3-
Polymorphism: No polymorphs are reported for imiquimod in literature to date.
Partition Coefficient: LogP = 3.01
Hygroscopicity: Not hygroscopic
Melting Point: 292-294°C
Composition:
Each gram of APO-IMIQUIMOD (imiquimod) cream contains 50 mg of imiquimod in a cream base consisting of benzyl alcohol, cetyl alcohol, glycerin, isostearic acid, methylparaben, polysorbate 60, propylparaben, purified water, sorbitan monostearate, stearyl alcohol, white petrolatum, and xanthan gum.
Stability and Storage Recommendations:
Store between 20-25°C (68°F to 77°F). Avoid freezing.
AVAILABILITY OF DOSAGE FORMS
APO-IMIQUIMOD (Imiquimod Cream) is available in single-use packets which contain 250 mg of the cream. It is available as a box of 12 or 24 packets.