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.

3 DOSAGE FORMS AND STRENGTHS ZYCLARA is a white to faintly yellow cream available as: • Cream: 2.5%, in pump bottles. Each pump bottle, when actuated after priming, delivers 0.235 grams of cream. • Cream: 3.75%, in unit-dose packets and pump bottles. Each packet contains 0.25 grams of cream and each pump bottle, when actuated after priming, delivers 0.235 grams of cream. Cream: 2.5% in pump bottles; 3.75% in pump bottles or unit-dose packets ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

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 …

8 USE IN SPECIFIC POPULATIONS 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). 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 ZYCLARA 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 ZYCLARA and any potential adverse effects on the breastfed infant from ZYCLARA or from the underlying maternal condition. Clinical Considerations Avoid application of ZYCLARA to areas with increased risk for potential ingestion by or ocular exposure to the breastfeeding child. 8.4 Pediatric Use Act …

12.1 Mechanism of Action The mechanism of action of ZYCLARA in the treatment of AK and EGW is unknown.

11 DESCRIPTION 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

10 OVERDOSAGE Topical overdosing of ZYCLARA could result in an increased incidence of severe local skin reactions and may increase the risk for systemic reactions. Hypotension was reported in a clinical trial following multiple oral imiquimod doses of >200 mg (equivalent to ingestion of the imiquimod content of more than 21 packets or pump actuations of ZYCLARA, 3.75% or more than 32 pump actuations of ZYCLARA, 2.5%). The hypotension resolved following oral or intravenous fluid administration. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ZYCLARA (imiquimod) cream is white to faintly yellow in color. ZYCLARA, 2.5% and 3.75% is supplied as white plastic 30 mL pump bottles, equipped with a white cap. The 7.5 g pump bottle delivers no fewer than 28 full actuations: • 2.5% cream, NDC 99207-276-75 • 3.75% cream, NDC 99207-271-75 ZYCLARA, 3.75% is also supplied in unit-dose plastic laminate packets which contain 0.25 g of cream: • 3.75% cream, box of 28 packets, NDC 99207-270-28 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.