Zyclara

1 INDICATIONS AND USAGE • 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.

2 DOSAGE AND ADMINISTRATION • 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.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS • 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 ZYCLARA and can occur after a few applications [ see Adverse Reactions (6) ]. Concomitant use of ZYCLARA and any other imiquimod products, in the same treatment area, may increase the risk for and severity of local skin reactions. ZYCLARA 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 ZYCLARA is on the skin. To reduce the risk of local skin reactions and manage local skin reactions that occur with ZYCLARA treatment: • Avoid concomitant use of ZYCLARA with any other imiquimod product in the same treatment area. • Avoid application of ZYCLARA 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 ZYCLARA for severe vulvar swelling [see Dosage and Administration (2.3 )]. • If severe local skin reactions occur, instruct patients to remove ZYCLARA 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 ZYCLARA 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 ZYCLARA 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 ZYCLARA, 3.75% and in 3% of subjects treated with ZYCLARA, 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 ZYCLARA may cause heightened sunburn susceptibility. Avoid or minimize exposure to sunlight (including sunlamps) during use of ZYCLARA. Instruct patients to use sunscreen and wear protective clothing (e.g., a hat). Advise patients not to use ZYCLARA 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 ZYCLARA.

6 ADVERSE REACTIONS 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) [ 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

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 ZYCLARA, 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).