ZYCLARA

ZYCLARA (imiquimod) cream, 2.5% or 3.75% is for topical administration. Each gram contains 25 mg or 37.5 mg of imiquimod, respectively, in a white to faintly yellow oil-in-water 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. Chemically, imiquimod is 1-(2-methylpropyl)-1 H -imidazol[4,5-c]quinolin-4-amine. Imiquimod has a molecular formula of C 14 H 16 N 4 and a molecular weight of 240.3. Its structural formula is: chem structure

ZYCLARA 2.5% and 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 ) ZYCLARA, 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 ZYCLARA, 2.5% and 3.75% are 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 ZYCLARA, 3.75% is indicated for the topical treatment of external genital and perianal warts (EGW) in immunocompetent patients 12 years of age and older.

For topical use only; not for oral, ophthalmic, intra-anal or intravaginal use. ( 2.1 ) AK : Apply a thin layer once daily at bedtime to affected area (either entire face or balding scalp) for two 2-week treatment cycles separated by a 2-week no-treatment period. Apply up to 0.5 grams at each application. ( 2.2 ) EGW : Apply a thin layer once daily at bedtime until total clearance or up to 8 weeks. Apply up to 0.25 grams at each application. ( 2.3 ) 2.1 Important Dosage and Administration Instructions ZYCLARA is for topical use only. ZYCLARA is not for oral, ophthalmic, intra-anal or intravaginal use. Instruct patients on proper application technique. Wash hands before and after applying ZYCLARA. Prime the ZYCLARA pump bottle before first use by repeatedly depressing the actuator until the cream is dispensed. It is not necessary to repeat this priming process during treatment. If a ZYCLARA dose is missed, apply the next dose at the regularly scheduled time. Avoid contact with the eyes, lips, nostrils, or inside the anus and vagina. Prescribe no more than 2 boxes (56 packets) or two 7.5 g bottle pumps of ZYCLARA for the entire treatment course for AK or EGW. Discard partially used packets and do not reuse. Discard pump bottles after completion of a full treatment course. 2.2 Dosage and Administration for Actinic Keratosis Use ZYCLARA, 2.5% or 3.75% for the treatment of AK. Apply a thin layer of ZYCLARA once daily before bedtime to the area with AK (either entire face or balding scalp) for two 2-week treatment cycles separated by a 2-week no-treatment period. Rub in until the cream is no longer visible. Apply up to 0.5 grams (two packets or two full actuations of the pump) of ZYCLARA at each application. Leave ZYCLARA on the skin for approximately 8 hours and then remove with mild soap and water. For local skin reactions, a dosage interruption of several days may be taken if required based on the patient’s discomfort or severity of the local skin reaction [see Warnings and Precautions (5.1 )] . Do not extend either 2-week treatment cycle due to missed doses or rest periods. Assess response to treatment after resolution of local skin reactions. A transient increase in lesion counts may be observed during treatment; however, continue dosing as prescribed. Continue treatment for the full treatment course even if all AK appear to be gone. 2.3 Dosage and Administration for External Genital Warts Use ZYCLARA, 3.75% for the treatment of EGW. Apply a thin layer of ZYCLARA cream once daily before bedtime to EGW until total clearance or for up to 8 weeks. To treat the wart area, use up to 0.25 grams (one packet or one full actuation of the pump) at each application. Leave ZYCLARA on the skin for approximately 8 hours and then remove with mild soap and water. For local skin reactions, a dosage interruption of several days may be taken if required by the patient's discomfort or severity of the local skin reaction; resume treatment once the reaction subsides [see Warnings and Precautions (5.1) ] . Non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions. Inform uncircumcised patients treating warts under the foreskin to retract the foreskin and clean the area daily. ZYCLARA may weaken condoms and vaginal diaphragms, therefore, concurrent use is not recommended.

None. None. ( 4 )

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 ZYCLARA 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 ZYCLARA, 3.75%, ZYCLARA, 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 ZYCLARA-Treated Subjects with AK and at a Greater Frequency than Vehicle in Studies AK1 and AK2 Adverse Reaction ZYCLARA, 3.75% (N=160) ZYCLARA, 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 ZYCLARA-Treated Subjects with AK as Assessed by the Investigator in Studies AK1 and AK2 All Grades* (%) Severe (%) ZYCLARA, 3.75% (N=160) ZYCLARA, 2.5% (N=160) Vehicle (N=159) Erythema Mild, moderate, or severe 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 ZYCLARA, 3.75% arm, 7% (11/160) of subjects in the ZYCLARA, 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 ZYCLARA 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 ZYCLARA, 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 ZYCLARA-Treated Subjects with EGW and at a Greater Frequency than Vehicle in Studies EGW1 and EGW2 Adverse Reaction ZYCLARA, 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* 6 (3%) 2 (2%) Headache 6 (2%) 1 (<1%) *Percentage based on female population of 6/216 for ZYCLARA, 3.75% and 2/106 for vehicle 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 ZYCLARA-Treated Subjects with EGW Assessed by the Investigator in Studies EGW1 and EGW2 All Grades* (%) Severe (%) ZYCLARA, 3.75% (N=400) Vehicle (N=202) Erythema Mild, moderate, or severe 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 ZYCLARA, 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 ZYCLARA, 3.75% discontinued treatment permanently due to local skin/application site reactions. Other adverse reactions reported in subjects treated with ZYCLARA, 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

Storage and Handling Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Avoid freezing. Store ZYCLARA pump bottles upright.