Imiquimod

Imiquimod Cream, 3.75% is indicated for the topical treatment of clinically typical, visible, or palpable actinic keratoses (AK) of the face or balding scalp in immunocompetent adults. ( 1.1 ) Imiquimod Cream, 3.75% is indicated for the topical treatment of external genital and perianal warts (EGW) in immunocompetent patients 12 years of age or older. ( 1.2 )

1.1 Actinic Keratosis Imiquimod Cream, 3.75% is indicated for the topical treatment of clinically typical, visible or palpable actinic keratoses (AK) of the face or balding scalp in immunocompetent adults.

1.2 External Genital Warts Imiquimod Cream, 3.75% is indicated for the topical treatment of external genital and perianal warts (EGW) in immunocompetent patients 12 years of age and older.

Imiquimod Cream, 3.75% is a white to faintly yellow cream available in pump bottles. Each pump bottle, when actuated after priming, delivers 0.235 grams of cream. Cream: 3.75% pump. ( 3 )

None. None. ( 4 )

Local Skin Reactions: Intense local inflammatory reactions can occur (e.g., skin weeping, erosion). Dosage interruption may be required. Severe vulvar swelling may occur and lead to urinary retention; interrupt dosing or discontinue for severe vulvar swelling. ( 2.2 , 2.3, 5.1 ) Systemic Reactions : Flu-like signs and symptoms have occurred. Consider dosage interruption for systemic reactions. ( 5.2 ) Ultraviolet Light Exposure Risks : Avoid or minimize exposure to sunlight and sunlamps. Wear protective clothing. ( 5.3 )

5.1 Local Skin Reactions Local skin reactions including skin weeping or erosion have been reported with use of Imiquimod Cream and can occur after a few applications [see Adverse Reactions (6)]. Concomitant use of Imiquimod Cream and any other imiquimod products, in the same treatment area, may increase the risk for and severity of local skin reactions. 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 and to urinary retention. Avoid sexual (genital, anal, oral) contact while Imiquimod Cream is on the skin. To reduce the risk of local skin reactions and manage local skin reactions that occur with Imiquimod Cream treatment: Avoid concomitant use of Imiquimod Cream with any other imiquimod product in the same treatment area. Avoid application of Imiquimod Cream 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 (2.2 , 2.3) ] . Interrupt dosing or discontinue Imiquimod Cream for severe vulvar swelling [see Dosage and Administration (2.3) ] . If severe local skin reactions occur, instruct patients to remove Imiquimod Cream by washing the treatment area with mild soap and water.

5.2 Systemic Reactions Flu-like signs and symptoms have been reported with use of Imiquimod Cream and may accompany, or even precede, local skin reactions [see Adverse Reactions (6) ] . Signs and symptoms may include fatigue, nausea, fever, myalgias, arthralgias, malaise and chills. Concomitant use of Imiquimod Cream and any other imiquimod products may increase the risk for and severity of systemic reactions. Lymphadenopathy occurred in 2% of subjects with AK treated with Imiquimod Cream, 3.75% and in 3% of subjects treated with Imiquimod Cream, 2.5% and in no patients in the vehicle arm [see Adverse Reactions (6.1) ]. This reaction resolved in all subjects by 4 weeks after completion of treatment. Consider an interruption of dosing if systemic reactions occur .

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

5.4 Immune Cell Activation in Autoimmune Disease Imiquimod activates immune cells [see Clinical Pharmacology (12.2) ] . Carefully monitor patients with pre-existing autoimmune conditions who are using Imiquimod Cream.

The following clinically significant adverse reactions are described elsewhere in the labeling: Local Skin Reactions [see Warnings and Precautions (5.1) ] Systemic Reactions [see Warnings and Precautions (5.2) ] Most common adverse reactions (≥4%) are local skin reactions (erythema, scabbing/crusting, flaking/scaling/dryness, edema, erosion/ulceration, exudate), headache, application site pain, application site irritation, application site pruritus, fatigue, influenza-like illness, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 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 479 subjects with AK enrolled in two double-blind, vehicle-controlled trials (Studies AK1 and AK2) [see Clinical Studies (14.1 )] . Subjects applied up to two packets of Imiquimod Cream, 3.75%, Imiquimod Cream, 2.5%, or vehicle once daily, to the skin of the affected area (either entire face or balding scalp) for two 2-week treatment cycles separated by a 2-week no treatment period. Selected adverse reactions are listed in Table 1. Table 1: Selected Adverse Reactions Occurring in ≥2% of Imiquimod Cream-Treated Subjects with AK and at a Greater Frequency than Vehicle in Studies AK1 and AK2 Adverse Reaction Imiquimod Cream, 3.75% (N=160) Imiquimod Cream, 2.5% (N=160) Vehicle (N=159) Headache 10 (6%) 3 (2%) 5 (3%) Application site pruritus 7 (4%) 6 (4%) 1 (<1%) Fatigue 7 (4%) 2 (1%) 0 Nausea 6 (4%) 1 (1%) 2 (1%) Application site irritation 5 (3%) 4 (3%) 0 Application site pain 5 (3%) 2 (1%) 0 Pyrexia 5 (3%) 0 0 Anorexia 4 (3%) 0 0 Dizziness 4 (3%) 1 (<1%) 0 Herpes simplex 4 (3%) 0 1 (<1%) Lymphadenopathy 3 (2%) 4 (3%) 0 Diarrhea 3 (2%) 2 (1%) 0 Arthralgia 2 (1%) 4 (3%) 0 Influenza like illness 1 (<1%) 6 (4%) 0 Oral herpes 0 4 (3%) 0 Cheilitis 0 3 (2%) 0 Local skin reactions were recorded as adverse reactions if they extended beyond the treatment area, or required any medical intervention, or resulted in patient discontinuation from the trial. The incidence and severity of selected local skin reactions are shown in Table 2. Table 2: Local Skin Reactions in the Treatment Area in Imiquimod Cream-Treated Subjects with AK as Assessed by the Investigator in Studies AK1 and AK2 All Grades Mild, moderate, or severe (%) Severe (%) Imiquimod Cream, 3.75% (N=160) Imiquimod Cream, 2.5% (N=160) Vehicle (N=159) Erythema Severe erythema 96% 25% 96% 14% 78% 0% Scabbing/Crusting Severe scabbing/crusting 93% 14% 84% 9% 45% 0% Flaking/Scaling/Dryness Severe flaking/scaling/dryness 91% 8% 88% 4% 77% 1% Edema Severe edema 75% 6% 63% 4% 19% 0% Erosion/Ulceration Severe erosion/ulceration 62% 11% 52% 9% 9% 0% Exudate Severe exudate 51% 6% 39% 1% 4% 0% In the AK trials, 11% (17/160) of subjects in the Imiquimod Cream, 3.75% arm, 7% (11/160) of subjects in the Imiquimod Cream, 2.5% arm, and 0% in the vehicle arm required rest periods due to adverse local skin reactions. Other adverse reactions observed in subjects treated with Imiquimod Cream included: application site bleeding, application site swelling, chills, dermatitis, herpes zoster, insomnia, lethargy, myalgia, pancytopenia, pruritus, squamous cell carcinoma, and vomiting. External Genital Warts In two double-blind, placebo-controlled trials 602 subjects with EGW applied up to one packet of Imiquimod Cream, 3.75% or vehicle to all warts once daily for up to 8 weeks (Studies EGW1 and EGW2) [see Clinical Studies (14.2) ] . The most frequently reported adverse reactions were application site reactions and local skin reactions. Selected adverse reactions are listed in Table 3. Table 3: Selected Adverse Reactions Occurring in ≥2% of Imiquimod Cream-Treated Subjects with EGW and at a Greater Frequency than Vehicle in Studies EGW1 and EGW2 Adverse Reaction Imiquimod Cream, 3.75% (N=400) Vehicle (N=202) Application site pain 28 (7%) 1 (<1%) Application site irritation 24 (6%) 2 (1%) Application site pruritus 11 (3%) 2 (1%) Vaginitis bacterial Percentage based on female population of 6/216 for Imiquimod Cream, 3.75% and 2/106 for vehicle 6 (3%) 2 (2%) Headache 6 (2%) 1 (<1%) Local skin reactions were recorded as adverse reactions if they extended beyond the treatment area, or required any medical intervention, or resulted in patient discontinuation from the trial. The incidence and severity of selected local skin reactions are shown in Table 4. Table 4: Selected Local Skin Reactions in the Treatment Area in Imiquimod Cream-Treated Subjects with EGW Assessed by the Investigator in Studies EGW1 and EGW2 All Grades Mild, moderate, or severe (%) Severe (%) Imiquimod Cream, 3.75% (N=400) Vehicle (N=202) Erythema Severe erythema 70% 9% 27% <1% Edema Severe edema 41% 2% 8% 0% Erosion/ulceration Severe erosion/ulceration 36% 11% 4% <1% Exudate Severe exudate 34% 2% 2% 0% The frequency and severity of local skin reactions were similar in both sexes, with the following exceptions: a) flaking/scaling occurred in 40% of males and in 26% of females and b) scabbing/crusting occurred in 34% of males and in 18% of females. In Studies EGW1 and EGW2, 32% (126/400) of subjects who used Imiquimod Cream, 3.75% and 2% (4/202) of subjects who used vehicle discontinued treatment temporarily (required rest periods) due to adverse local skin reactions, and 1% (3/400) of subjects who used Imiquimod Cream, 3.75% discontinued treatment permanently due to local skin/application site reactions. Other adverse reactions reported in subjects treated with Imiquimod Cream, 3.75% included: rash, back pain, application site rash, application site cellulitis, application site excoriation, application site bleeding, scrotal pain, scrotal erythema, scrotal ulcer, scrotal edema, sinusitis, nausea, pyrexia, and influenza-like symptoms.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of imiquimod. 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, supraventricular 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, urinary retention, dysuria Skin and Appendages : exfoliative dermatitis, erythema multiforme, hyperpigmentation, hypertrophic scar, hypopigmentation Vascular : Henoch-Schönlein purpura syndrome

8.1 Pregnancy Risk Summary Available data from case reports and case series have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes when imiquimod is used during pregnancy. 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 28 times and 115 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 defects, loss, and 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 two packets per treatment of Imiquimod Cream, 3.75%, (18.75 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 (163 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 (28 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 (2.1 times the MRHD based on BSA comparison), the highest dose evaluated in this study, or 1 mg/kg/day (115 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 (25 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 (25 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 (12 times the MRHD based on AUC comparison).

8.2 Lactation Risk Summary There is no information regarding the presence of topically administered imiquimod in human milk, the effects on the breastfed infant, or the effects on milk production. Systemic concentration following topical administration of imiquimod cream is low; therefore, transfer of Imiquimod Cream into breastmilk is likely to be low [see Clinical Pharmacology (12.3) ]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Imiquimod Cream and any potential adverse effects on the breastfed infant from Imiquimod Cream or from the underlying maternal condition. Clinical Considerations Avoid application of Imiquimod Cream to areas with increased risk for potential ingestion by or ocular exposure to the breastfeeding child.

8.4 Pediatric Use Actinic Keratosis The safety and effectiveness of Imiquimod Cream for the treatment of AK in pediatric patients have not been established. External Genital Warts The safety and effectiveness of Imiquimod Cream for the treatment of EGW in pediatric patients 12 years of age and older have been established. Use of Imiquimod Cream for this indication is supported by evidence from adequate and well controlled trials in adults and pediatric subjects [see Clinical Studies (14.2) ] . The safety and effectiveness of Imiquimod Cream 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 Imiquimod Cream for the treatment of molluscum contagiosum (MC) in pediatric patients have not been established. Safety and effectiveness of imiquimod cream, 5% was not demonstrated in two randomized, vehicle-controlled, double-blind trials involving 702 pediatric subjects with MC (470 exposed to imiquimod cream; median age 5 years, range 2-12 years). Adverse reactions reported in pediatric subjects with MC (and not previously reported) included otitis media (5% imiquimod cream vs. 3% vehicle) and conjunctivitis (3% imiquimod cream 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 10 9 /L and the median absolute neutrophil count decreased by 1.42 x 10 9 /L.

8.5 Geriatric Use Of the 320 subjects treated with Imiquimod Cream in the AK clinical trials, 150 subjects (47%) were 65 years of age or older. No overall differences in safety or effectiveness of Imiquimod Cream have been observed between subjects 65 years of age and older and younger adult subjects. Of the 400 subjects treated with Imiquimod Cream in the EGW clinical studies, 5 subjects (1%) were 65 years or older. Clinical studies of Imiquimod Cream for EGW did not include sufficient numbers of subjects aged 65 years of age and older to determine whether they respond differently from younger adult subjects.

The mechanism of action of Imiquimod Cream in the treatment of AK and EGW is unknown.